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Blümke J, Schameitat M, Verma A, Limbecker C, Arlt E, Kessler SM, Kielstein H, Krug S, Bazwinsky-Wutschke I, Haemmerle M. Innate Immunity and Platelets: Unveiling Their Role in Chronic Pancreatitis and Pancreatic Cancer. Cancers (Basel) 2025; 17:1689. [PMID: 40427186 PMCID: PMC12110028 DOI: 10.3390/cancers17101689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2025] [Revised: 05/10/2025] [Accepted: 05/14/2025] [Indexed: 05/29/2025] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal forms of cancer, characterized by a highly desmoplastic tumor microenvironment. One main risk factor is chronic pancreatitis (CP). Progression of CP to PDAC is greatly influenced by persistent inflammation promoting genomic instability, acinar-ductal metaplasia, and pancreatic intraepithelial neoplasia (PanIN) formation. Components of the extracellular matrix, including immune cells, can modulate this progression phase. This includes cells of the innate immune system, such as natural killer (NK) cells, macrophages, dendritic cells, mast cells, neutrophils, and myeloid-derived suppressor cells (MDSCs), either promoting or inhibiting tumor growth. On one hand, innate immune cells can trigger inflammatory responses that support tumor progression by releasing cytokines and growth factors, fostering tumor cell proliferation, invasion, and metastasis. On the other hand, they can also activate immune surveillance mechanisms, which can limit tumor development. For example, NK cells are cytotoxic innate lymphoid cells that are able to kill tumor cells, and active dendritic cells are crucial for a functioning anti-tumor immune response. In contrast, mast cells and MDSCs rather support a pro-tumorigenic tumor microenvironment that is additionally sustained by platelets. Once thought to play a role in hemostasis only, platelets are now recognized as key players in inflammation and cancer progression. By releasing cytokines, growth factors, and pro-angiogenic mediators, platelets help shape an immunosuppressive microenvironment that promotes fibrotic remodeling, tumor initiation, progression, metastasis, and immune evasion. Neutrophils and macrophages exist in different functional subtypes that can both act pro- and anti-tumorigenic. Understanding the complex interactions between innate immune cells, platelets, and early precursor lesions, as well as PDAC cells, is crucial for developing new therapeutic approaches that can harness the immune and potentially also the coagulation system to target and eliminate tumors, offering hope for improved patient outcomes.
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Affiliation(s)
- Juliane Blümke
- Institute of Pathology, Section of Experimental Pathology, Medical Faculty, Martin Luther University Halle-Wittenberg, 06112 Halle (Saale), Germany;
| | - Moritz Schameitat
- Institute of Anatomy and Cell Biology, Medical Faculty, Martin Luther University Halle-Wittenberg, 06108 Halle (Saale), Germany; (M.S.); (C.L.); (H.K.); (I.B.-W.)
| | - Atul Verma
- Department of Internal Medicine I, Medical Faculty, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany; (A.V.); (S.K.)
| | - Celina Limbecker
- Institute of Anatomy and Cell Biology, Medical Faculty, Martin Luther University Halle-Wittenberg, 06108 Halle (Saale), Germany; (M.S.); (C.L.); (H.K.); (I.B.-W.)
| | - Elise Arlt
- Institute of Anatomy and Cell Biology, Medical Faculty, Martin Luther University Halle-Wittenberg, 06108 Halle (Saale), Germany; (M.S.); (C.L.); (H.K.); (I.B.-W.)
| | - Sonja M. Kessler
- Institute of Pharmacy, Experimental Pharmacology for Natural Sciences, Faculty of Natural Sciences, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany;
| | - Heike Kielstein
- Institute of Anatomy and Cell Biology, Medical Faculty, Martin Luther University Halle-Wittenberg, 06108 Halle (Saale), Germany; (M.S.); (C.L.); (H.K.); (I.B.-W.)
| | - Sebastian Krug
- Department of Internal Medicine I, Medical Faculty, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany; (A.V.); (S.K.)
- Department of Internal Medicine IV, University Hospital Heidelberg, 69120 Heidelberg, Germany
| | - Ivonne Bazwinsky-Wutschke
- Institute of Anatomy and Cell Biology, Medical Faculty, Martin Luther University Halle-Wittenberg, 06108 Halle (Saale), Germany; (M.S.); (C.L.); (H.K.); (I.B.-W.)
| | - Monika Haemmerle
- Institute of Pathology, Section of Experimental Pathology, Medical Faculty, Martin Luther University Halle-Wittenberg, 06112 Halle (Saale), Germany;
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2
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Yan B, Fritsche AK, Haußner E, Inamdar TV, Laumen H, Boettcher M, Gericke M, Michl P, Rosendahl J. From Genes to Environment: Elucidating Pancreatic Carcinogenesis Through Genetically Engineered and Risk Factor-Integrated Mouse Models. Cancers (Basel) 2025; 17:1676. [PMID: 40427173 PMCID: PMC12110317 DOI: 10.3390/cancers17101676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2025] [Revised: 05/07/2025] [Accepted: 05/13/2025] [Indexed: 05/29/2025] Open
Abstract
Pancreatic cancer is characterized by late diagnosis, therapy resistance, and poor prognosis, necessitating the exploration of early carcinogenesis and prevention methods. Preclinical mouse models have evolved from cell line-based to human tumor tissue- or organoid-derived xenografts, now to humanized mouse models and genetically engineered mouse models (GEMMs). GEMMs, primarily driven by oncogenic Kras mutations and tumor suppressor gene alterations, offer a realistic platform for investigating pancreatic cancer initiation, progression, and metastasis. The incorporation of inducible somatic mutations and CRISPR-Cas9 screening methods has expanded their utility. To better recapitulate tumor initiation triggered by inflammatory cues, common pancreatic risk factors are being integrated into model designs. This approach aims to decipher the role of environmental factors as secondary or parallel triggers of tumor initiation alongside oncogenic burdens. Emerging models exploring pancreatitis, obesity, diabetes, and other risk factors offer significant translational potential. This review describes current mouse models for studying pancreatic carcinogenesis, their combination with inflammatory factors, and their utility in evaluating pathogenesis, providing guidance for selecting the most suitable models for pancreatic cancer research.
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Affiliation(s)
- Bin Yan
- Department of Internal Medicine IV, Heidelberg University Hospital, 69120 Heidelberg, Germany;
| | - Anne-Kristin Fritsche
- Institute of Anatomy and Cell Biology, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany;
- Institute of Anatomy, Leipzig University, 04103 Leipzig, Germany;
| | - Erik Haußner
- Institute of Molecular Medicine, Section for Molecular Medicine of Signal Transduction, Faculty of Medicine, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany; (E.H.); (M.B.)
| | - Tanvi Vikrant Inamdar
- Department of Internal Medicine I, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany; (T.V.I.); (H.L.)
| | - Helmut Laumen
- Department of Internal Medicine I, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany; (T.V.I.); (H.L.)
| | - Michael Boettcher
- Institute of Molecular Medicine, Section for Molecular Medicine of Signal Transduction, Faculty of Medicine, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany; (E.H.); (M.B.)
| | - Martin Gericke
- Institute of Anatomy, Leipzig University, 04103 Leipzig, Germany;
| | - Patrick Michl
- Department of Internal Medicine IV, Heidelberg University Hospital, 69120 Heidelberg, Germany;
| | - Jonas Rosendahl
- Department of Internal Medicine I, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany; (T.V.I.); (H.L.)
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3
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Chang DH, Wang F, Palecek SP, Lynn DM. Slippery Liquid-Infused Porous Surfaces Infused with Thermotropic Liquid Crystals Enable Droplet-Based, Naked-Eye Reporting of Changes in Peptide Structure and Protease Activity. ACS APPLIED MATERIALS & INTERFACES 2025; 17:27882-27894. [PMID: 40314309 PMCID: PMC12101578 DOI: 10.1021/acsami.5c02541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 05/03/2025]
Abstract
We report the design of liquid crystal-infused "slippery" liquid-infused porous surfaces (LC-SLIPS) that permit naked-eye detection and reporting on the structural differences and activities of peptides and protease enzymes in aqueous media. We demonstrate that small (e.g., 20 μL) droplets of aqueous solutions placed in contact with LC-SLIPS exhibit sliding behaviors that vary substantially with the concentrations, structures, and physicochemical properties (e.g., hydrophobicity) of model amphiphilic β- and α/β-peptides dissolved within them. These large differences in sliding times permit naked-eye detection and discrimination of changes in peptide structure, including side-chain substitution, end group structure, backbone structure, and charge that correlate with differences in peptide amphiphilicity. We demonstrate further that LC-SLIPS can be used to monitor other biochemical processes, including digestion by proteases, that affect changes in the structures of amphiphilic peptides and can, thus, be used to develop novel, naked-eye assays that can report sensitively on enzymatic activity. As proof of concept, we show that large and visually observable changes in droplet sliding resulting from the degradation of a model peptide can be used to detect the presence of trypsin in aqueous solutions at levels as low as 12.5 ng/mL. That result, in turn, served as the basis of an LC-SLIPS-based assay that can be used to detect clinically relevant concentrations (from 25 to 25,000 ng/mL) of trypsinogen, a well-established biomarker for acute pancreatitis, in samples of synthetic urine. This "sliding" assay is conceptually straightforward and requires only visual monitoring and/or a hand-held stopwatch for readout, highlighting the potential for low-cost, point-of-care diagnostics applications. Overall, our results demonstrate the ability of LC-SLIPS to capture and report structural information relevant to other therapeutic properties and applications of amphiphilic peptides that could also be useful in the context of drug design and screening.
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Affiliation(s)
- Douglas H Chang
- Department of Chemical and Biological Engineering, University of Wisconsin-Madison, 1415 Engineering Dr., Madison, Wisconsin 53706, United States
| | - Fengrui Wang
- Department of Chemistry, University of Wisconsin-Madison, 1101 University Ave., Madison, Wisconsin 53706, United States
| | - Sean P Palecek
- Department of Chemical and Biological Engineering, University of Wisconsin-Madison, 1415 Engineering Dr., Madison, Wisconsin 53706, United States
| | - David M Lynn
- Department of Chemical and Biological Engineering, University of Wisconsin-Madison, 1415 Engineering Dr., Madison, Wisconsin 53706, United States
- Department of Chemistry, University of Wisconsin-Madison, 1101 University Ave., Madison, Wisconsin 53706, United States
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Zottl J, Sebesta CG, Tomosel E, Sebesta MC, Sebesta C. Unraveling the Burden of Pancreatic Cancer in the 21st Century: Trends in Incidence, Mortality, Survival, and Key Contributing Factors. Cancers (Basel) 2025; 17:1607. [PMID: 40427106 PMCID: PMC12110279 DOI: 10.3390/cancers17101607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2025] [Revised: 05/01/2025] [Accepted: 05/05/2025] [Indexed: 05/29/2025] Open
Abstract
Background: PC has become a significant global health challenge, with incidence and mortality rates rising over the past three decades. While traditionally associated with aging, recent data indicate an increasing burden among younger populations. This study aims to analyze global trends in PC incidence and mortality and to identify key contributing factors, particularly modifiable risk factors such as obesity, diabetes, and smoking. Methods: Using data from the Global Burden of Disease Study (GBD) 2021, population-based cancer registries globally and nationally, systematic reviews and analysis trends in PC incidence, mortality and survival were analyzed. To assess epidemiological shifts, we utilized previously published annual percentage change (AAPC) values stratified by region, age group, and sex, as reported in the cited literature. Additionally, the influence of modifiable risk factors was evaluated to determine their contribution to rising incidence rates. Results: Between 1990 and 2021, the global incidence of PC increased by 8.9%, from 5.47 to 5.96 per 100,000, with the highest rates observed in high-Sociodemographic-Index (SDI) regions (10.00 per 100,000) and the lowest in low-SDI regions (1.59 per 100,000). Significant increases in incidence were noted in several countries, particularly among men in Iceland (AAPC 8.85) and women in Malta (AAPC 6.04). Early-onset PC is becoming more prevalent, especially among younger women. Modifiable risk factors, including obesity, diabetes, and smoking, play a critical role, with excess body weight contributing to 17.9% of PC cases and smoking to 13.9% in the United States (U.S.). Conclusions: The rising burden of PC, particularly among younger populations, highlights the need for targeted prevention strategies, early detection efforts, and further research into the underlying mechanisms driving these trends. Addressing modifiable risk factors could be key to mitigating the increasing incidence of this highly lethal cancer.
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Affiliation(s)
- Jakob Zottl
- Science Center Donaustadt, 1220 Vienna, Austria; (C.G.S.); (M.-C.S.)
| | | | - Elena Tomosel
- 2nd Medical Departement, Klinik Donaustadt, Science Center Donaustadt, 1220 Vienna, Austria;
| | | | - Christian Sebesta
- 2nd Medical Departement, Klinik Donaustadt, Science Center Donaustadt, Vienna Cancer Center (VCC), 1220 Vienna, Austria;
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5
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Winterroth F, Wang J, Wink O, Carelsen B, Dahl J, Thakor AS. A Theoretical Approach in Applying High-Frequency Acoustic and Elasticity Microscopy to Assess Cells and Tissues. Annu Rev Biomed Eng 2025; 27:283-305. [PMID: 39971347 DOI: 10.1146/annurev-bioeng-112823-103134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Medical ultrasound is a diagnostic imaging modality used for visualizing internal organs; the frequencies typically used are 2-10 MHz. Scanning acoustic microscopy (SAM) is a form of ultrasound where frequencies typically exceed 50 MHz. Increasing the acoustic frequency increases the specimen's spatial resolution but reduces the imaging depth. The advantages of using SAM over conventional light and electron microscopy include the ability to image cells and tissues without any preparation that could kill or alter them, providing a more accurate representation of the specimen. After scanning the specimen, acoustic signals are merged into an image on the basis of changes in the impedance mismatch between the immersion fluid and the specimens. The acoustic parameters determining the image quality are absorption and scattering. Surface scans can assess surface characteristics of the specimen. SAM is also capable of elastography, that is, studying elastic properties to discern differences between healthy and affected tissues. SAM has significant potential for detection/analysis in research and clinical studies.
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Affiliation(s)
| | - Jing Wang
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University School of Medicine, Palo Alto, California, USA
| | - Onno Wink
- Philips Research, Eindhoven, The Netherlands;
| | | | - Jeremy Dahl
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University School of Medicine, Palo Alto, California, USA
| | - Avnesh S Thakor
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University School of Medicine, Palo Alto, California, USA
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Dovhalyuk V, Yang F, Nikolic S, Vujasinovic M, Löhr JM, Globisch D. Differences in the Fecal Metabolome of Autoimmune Pancreatitis Patients. United European Gastroenterol J 2025. [PMID: 40243134 DOI: 10.1002/ueg2.70025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 02/08/2025] [Accepted: 02/16/2025] [Indexed: 04/18/2025] Open
Abstract
BACKGROUND Chronic pancreatitis is a risk factor for pancreatic cancer. Autoimmune pancreatitis is a unique form of chronic pancreatitis that is primarily characterized by its immune mediate etiology, clinically resembling pancreatic cancer, yet uniquely responsive to steroid treatment. OBJECTIVE Early and accurate diagnosis of autoimmune pancreatitis is vital for effective treatment and patient prognosis, for which new diagnostic tools are urgently required. Gut microbiota dysbiosis has been identified to correlate with the development of pancreatic diseases, which provides new opportunities for the discovery of disease biomarkers. METHODS We utilized a mass spectrometric global metabolomics investigation of patient autoimmune pancreatitis and chronic pancreatitis fecal samples, investigating microbiome, dietary and human metabolism. RESULTS We discovered a series of newly identified metabolic signatures between both patient groups including enterolactone, 4-guanidinobutanoic acid, and methylthioadenosine sulfoxide. Additionally, the analysis revealed significant differences in several metabolic pathways such as fatty acids, alkaloids, amino acids and peptides. CONCLUSION Our observations provide novel insights into important metabolic human pathways and microbiome-derived metabolites to distinguish autoimmune pancreatitis from chronic pancreatitis. These findings reveal systemic metabolic responses and the identified metabolites may be developed into potential biomarkers for future diagnosis to distinguish between autoimmune pancreatitis and chronic pancreatitis.
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Affiliation(s)
- Vladyslav Dovhalyuk
- Department of Chemistry - BMC, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Fan Yang
- Department of Chemistry - BMC, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Sara Nikolic
- Department of Gastroenterology, Clinic of Internal Medicine, University Medical Centre Maribor, Maribor, Slovenia
- Department of Medicine Huddinge, Karolinska Institute, Stockholm, Sweden
| | - Miroslav Vujasinovic
- Department of Medicine Huddinge, Karolinska Institute, Stockholm, Sweden
- Department for Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - J-Matthias Löhr
- Department for Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden
- Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute, Stockholm, Sweden
| | - Daniel Globisch
- Department of Chemistry - BMC, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
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7
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Yi F, Tao S, Wu H. Bilirubin metabolism in relation to cancer. Front Oncol 2025; 15:1570288. [PMID: 40291905 PMCID: PMC12021636 DOI: 10.3389/fonc.2025.1570288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Accepted: 03/11/2025] [Indexed: 04/30/2025] Open
Abstract
Bilirubin, a metabolite of hemoglobin, was long thought to be a harmful waste product, but recent studies have found it to have antioxidant and anti-tumor effects. With the extensive research on the mechanism of malignant tumor development, the antioxidant effect of bilirubin is increasingly becoming a hotspot in anti-cancer research. At present, there are two main views on the relationship between bilirubin and cancer, namely, its pro-cancer and anti-cancer effects, and in recent years, studies on the relationship between bilirubin and cancer have not been systematically summarized, which is not conducive to the further investigation of the role of bilirubin on cancer. To understand the multifaceted role of bilirubin in tumorigenesis as well as to develop more effective and affordable antitumor therapies, this review provides an overview of the effects of bilirubin on tumors in terms of oxidative, inflammatory, and cellular signaling pathways, as well as the resulting therapeutic ideas and approaches.
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Affiliation(s)
- Fengyun Yi
- Department of Traditional Chinese Medicine, Jiujiang Hospital of Traditional Chinese Medicine, Jiujiang, Jiangxi, China
- The Second School of Clinical Medicine, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Siyu Tao
- The Second School of Clinical Medicine, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Hongze Wu
- Department of Traditional Chinese Medicine, Jiujiang Hospital of Traditional Chinese Medicine, Jiujiang, Jiangxi, China
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8
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Sastre J, Pérez S, Sabater L, Rius-Pérez S. Redox signaling in the pancreas in health and disease. Physiol Rev 2025; 105:593-650. [PMID: 39324871 DOI: 10.1152/physrev.00044.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 09/11/2024] [Accepted: 09/17/2024] [Indexed: 09/27/2024] Open
Abstract
This review addresses oxidative stress and redox signaling in the pancreas under healthy physiological conditions as well as in acute pancreatitis, chronic pancreatitis, pancreatic cancer, and diabetes. Physiological redox homeodynamics is maintained mainly by NRF2/KEAP1, NF-κB, protein tyrosine phosphatases, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α), and normal autophagy. Depletion of reduced glutathione (GSH) in the pancreas is a hallmark of acute pancreatitis and is initially accompanied by disulfide stress, which is characterized by protein cysteinylation without increased glutathione oxidation. A cross talk between oxidative stress, MAPKs, and NF-κB amplifies the inflammatory cascade, with PP2A and PGC1α as key redox regulatory nodes. In acute pancreatitis, nitration of cystathionine-β synthase causes blockade of the transsulfuration pathway leading to increased homocysteine levels, whereas p53 triggers necroptosis in the pancreas through downregulation of sulfiredoxin, PGC1α, and peroxiredoxin 3. Chronic pancreatitis exhibits oxidative distress mediated by NADPH oxidase 1 and/or CYP2E1, which promotes cell death, fibrosis, and inflammation. Oxidative stress cooperates with mutant KRAS to initiate and promote pancreatic adenocarcinoma. Mutant KRAS increases mitochondrial reactive oxygen species (ROS), which trigger acinar-to-ductal metaplasia and progression to pancreatic intraepithelial neoplasia (PanIN). ROS are maintained at a sufficient level to promote cell proliferation, while avoiding cell death or senescence through formation of NADPH and GSH and activation of NRF2, HIF-1/2α, and CREB. Redox signaling also plays a fundamental role in differentiation, proliferation, and insulin secretion of β-cells. However, ROS overproduction promotes β-cell dysfunction and apoptosis in type 1 and type 2 diabetes.
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Affiliation(s)
- Juan Sastre
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
| | - Salvador Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
| | - Luis Sabater
- Liver, Biliary and Pancreatic Unit, Hospital Clínico, Department of Surgery, Faculty of Medicine, University of Valencia, Valencia, Spain
| | - Sergio Rius-Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
- Department of Cell Biology, Functional Biology and Physical Anthropology, Faculty of Biology, University of Valencia, Valencia, Spain
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9
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Ma Z, Hua J, Wei M, Han L, Dong M, Xie W, Luo T, Meng Q, Wang W, Song Z, Shi S, Yu X, Xu J. The pancreatitis-cancer transformation-related factor, human rhomboid family-1, promotes pancreatic cancer progression through the SRC/YAP signaling pathway. Transl Oncol 2025; 54:102346. [PMID: 40056528 PMCID: PMC11930795 DOI: 10.1016/j.tranon.2025.102346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 03/01/2025] [Accepted: 03/03/2025] [Indexed: 03/10/2025] Open
Abstract
Pancreatic cancer is an aggressive malignancy characterized by rapid progression, unfavorable outcomes, and a low early detection rate. Elucidating the mechanisms underlying the onset and progression of pancreatic tumors is essential for early detection and for developing preventive measures. Even though human rhomboid family-1 (RHBDF) acts as an oncogene in various tumors, the role of RHBDF in pancreatic cancer progression remains unexplored. Here, publicly available datasets, including samples of chronic pancreatitis associated with pancreatic cancer from our center, were used for bioinformatics analyses, including differential expression, survival, and enrichment studies. The findings were validated by immunohistochemical staining and in vitro experiments. We found that RHBDF1 was significantly upregulated in tumor samples relative to adjacent non-tumor and pancreatitis tissues, and its expression increased in correlation with the progression of pancreatitis to cancer. Furthermore, RHBDF1 promoted the proliferation, migration, and invasion of pancreatic cancer cells, and in vivo studies demonstrated that RHBDF1 promoted pancreatic cancer progression, tissue fibrosis, and the formation of new blood vessels. RNA-sequencing and cell functional experiments indicated that RHBDF1 promotes the progression of pancreatic cancer through the SRC-YAP signaling pathway. In summary, the pancreatitis-cancer transformation-related factor, RHBDF1, promotes pancreatic cancer progression by activating the SRC-YAP signaling cascade, indicating that RHBDF1 could be a viable target for the diagnosis and treatment of early-stage pancreatic cancer.
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Affiliation(s)
- Zhilong Ma
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Jie Hua
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Miaoyan Wei
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Lin Han
- Central Laboratory, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China
| | - Mingwei Dong
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Wangcheng Xie
- Department of Hepatopancreatobiliary Surgery, Shanghai Fourth People's Hospital, Tongji University School of Medicine, Shanghai 200434, China
| | - Tingyi Luo
- Department of Hepatopancreatobiliary Surgery, Shanghai Fourth People's Hospital, Tongji University School of Medicine, Shanghai 200434, China
| | - Qingcai Meng
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Wei Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Zhenshun Song
- Department of Hepatopancreatobiliary Surgery, Shanghai Fourth People's Hospital, Tongji University School of Medicine, Shanghai 200434, China
| | - Si Shi
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
| | - Jin Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
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10
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Bampton TJ, Chen JW, Brown A, Barnett MI, Coates PT, Palmer LJ. Epidemiology and burden of adult chronic pancreatitis in South Australia: a 20-year data linkage study. BMJ Open 2025; 15:e089297. [PMID: 40050052 PMCID: PMC11887304 DOI: 10.1136/bmjopen-2024-089297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 01/24/2025] [Indexed: 03/09/2025] Open
Abstract
OBJECTIVES To investigate the epidemiology and burden of adult-onset chronic pancreatitis (CP) in South Australia. DESIGN Retrospective case-control study; data linkage. SETTING All public adult hospitals in SA. PARTICIPANTS Administrative data linkage from South Australia-Northern Territory DataLink was used to ascertain an index cohort of all adults with an initial diagnosis of CP aged >19 years between June 2000 and June 2019. Age- and sex-matched controls were drawn from the general population of SA, adults with type 1 diabetes mellitus and adults with type 2 diabetes mellitus (defined by International Classification of Diseases 10th Revision coding). MAIN OUTCOME MEASURES Hospital visits, days in hospital, emergency department visits, intensive care unit admissions, incidence, prevalence. RESULTS A total of 2503 incident index cases with CP were identified. The crude prevalence and incidence were estimated as 195.1 per 100 000 and 10.4 per 100 000 per annum, respectively. Cases of CP averaged more hospital visits for any reason (median 11, IQR 5 to 21.75) than the general population (median 1, IQR 0 to 4) and had a higher healthcare burden than controls with type 1 diabetes or type 2 diabetes (all p<0.001). Indigenous individuals were over-represented in the cohort (n=358; 14.8% vs 1.5% of the general population) and had higher healthcare utilisation than other patients with CP (p<0.001). CONCLUSIONS CP is a significant burden on the SA healthcare system and was more prevalent and more burdensome in Indigenous adults. CP consumes a disproportionate level of public health services. Our findings support further research and preventive efforts, particularly in the Indigenous population.
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Affiliation(s)
- Tristan J Bampton
- School of Public Health, The University of Adelaide, Adelaide, South Australia, Australia
| | - John W Chen
- Department of Surgery, Flinders Medical Centre, Bedford Park, Australia
| | - Alex Brown
- Australian National University, Canberra, Australia
| | - Meghan I Barnett
- School of Medicine, The University of Adelaide, Adelaide, South Australia, Australia
| | - P Toby Coates
- Central Northern Adelaide Renal and Transplantation Service, Royal Adelaide Hospital, Adelaide, South Australia, Australia
- School of Medicine, The University of Adelaide, Adelaide, South Australia, Australia
| | - Lyle John Palmer
- School of Public Health, The University of Adelaide, Adelaide, South Australia, Australia
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11
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Mohamed G, Munir M, Rai A, Gaddam S. Pancreatic Cancer: Screening and Early Detection. Gastroenterol Clin North Am 2025; 54:205-221. [PMID: 39880528 DOI: 10.1016/j.gtc.2024.09.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2025]
Abstract
Pancreatic cancer, often diagnosed at advanced stages, has poor survival rates. Effective screening aims to detect the disease early, improving outcomes. Current guidelines recommend screening high-risk groups, including those with a family history or genetic predispositions, using methods like endoscopic ultrasound and MRI. The American Gastroenterological Association and other organizations advise annual surveillance for high-risk individuals, typically starting at the age of 50 or 10 years younger than the youngest affected relative. For certain genetic syndromes, such as Peutz-Jeghers syndrome or hereditary pancreatitis, screening may begin as early as the age of 35 to 40 years.
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Affiliation(s)
- Ghada Mohamed
- Department of Internal Medicine, Lahey Hospital & Medical Center, 41 Mall Road, Burlington, MA 01805, USA
| | - Malak Munir
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, ST, Suite 7705, Los Angeles, CA 90048, USA
| | - Amar Rai
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, ST, Suite 7705, Los Angeles, CA 90048, USA
| | - Srinivas Gaddam
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, ST, Suite 7705, Los Angeles, CA 90048, USA.
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12
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Cardinal von Widdern J, Knoph CS, Kase K, Regel I, Rosendahl J, Ammer-Hermenau C, Nikolic S. Autoimmune pancreatitis, pancreatic and extrapancreatic cancer (AIPPEAR): a multicentre, retrospective study protocol. BMJ Open 2025; 15:e086824. [PMID: 39956600 PMCID: PMC11831303 DOI: 10.1136/bmjopen-2024-086824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2024] [Accepted: 01/29/2025] [Indexed: 02/18/2025] Open
Abstract
INTRODUCTION Autoimmune pancreatitis (AIP) mainly manifests in two distinct forms with different clinical, serological and prognostic characteristics. Previous studies indicated a higher risk of malignancy in AIP patients compared with the general population. However, a direct comparison of cancer incidence in AIP patients with controls from the general population has not been conducted yet. METHODS AND ANALYSIS This is an international, multicentre, retrospective study on patients diagnosed with AIP after 2005. Retrospective data regarding demography, AIP characteristics and cancer incidence will be extracted from the medical files of AIP patients. The primary outcome is the standardised incidence ratio of any first invasive cancer after AIP diagnosis compared with the general population. The expected number of cancers in the general population will be determined using the 'Cancer Incidence in Five Continents Volume XI' registry. Secondary outcomes are the prevalence of all cancer diagnoses within 12 months prior to AIP diagnosis and AIP features associated with a cancer diagnosis. ETHICS AND DISSEMINATION This study was approved by the ethics committees of the autoimmune pancreatitis, pancreatic and extrapancreatic cancer (AIPPEAR) core group centres (Halle (Saale), Germany; Aalborg, Denmark; Tartu, Estonia; Munich, Germany; Göttingen, Germany; Maribor, Slovenia, with the following reference numbers: 2023-204, 2023-0 29 953, 382 /T-3, 24-0768, 9/7/23, UKC-MB-KME 59/23, respectively). Where required, the study protocol will be reviewed and approved by the ethics committees of participating centres in compliance with local regulations. Data will be stored in an electronic case report form within REDCap. In this context, the AIPPEAR core group will share joint responsibility for the data. All results from this study will be submitted to international, peer-reviewed journals and presented at international conferences. TRIAL REGISTRATION NUMBER NCT06328101.
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Affiliation(s)
- Julian Cardinal von Widdern
- Department for Internal Medicine I (Gastroenterology, Pulmonology), University Hospital Halle Department of Internal Medicine, Halle, Germany
| | - Cecilie Siggaard Knoph
- Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Karri Kase
- Department of General and Plastic Surgery, Tartu University Hospital, Tartu, Estonia
| | - Ivonne Regel
- Department of Medicine II, University Hospital of Munich, Munchen, Germany
| | - Jonas Rosendahl
- Department for Internal Medicine I (Gastroenterology, Pulmonology), University Hospital Halle Department of Internal Medicine, Halle, Germany
| | - Christoph Ammer-Hermenau
- Department for Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Hospital Göttingen, Göttingen, Germany
| | - Sara Nikolic
- Department of Gastroenterology and Endoscopy, University Medical Center Maribor, Maribor, Slovenia
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13
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Vujasinovic M, Maisonneuve P, Löhr JM. Ensuring timely detection of neoplastic transformation by surveilling chronic pancreatitis. Best Pract Res Clin Gastroenterol 2025; 74:101985. [PMID: 40210332 DOI: 10.1016/j.bpg.2025.101985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 01/08/2025] [Accepted: 01/24/2025] [Indexed: 03/03/2025]
Affiliation(s)
- Miroslav Vujasinovic
- Department of Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden; Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
| | - Patrick Maisonneuve
- Division of Epidemiology and Biostatistics, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - J-Matthias Löhr
- Department of Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
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14
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Malnassy G, Ziolkowski L, Macleod KF, Oakes SA. The Integrated Stress Response in Pancreatic Development, Tissue Homeostasis, and Cancer. Gastroenterology 2024; 167:1292-1306. [PMID: 38768690 PMCID: PMC11570703 DOI: 10.1053/j.gastro.2024.05.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 04/06/2024] [Accepted: 05/02/2024] [Indexed: 05/22/2024]
Abstract
Present in all eukaryotic cells, the integrated stress response (ISR) is a highly coordinated signaling network that controls cellular behavior, metabolism, and survival in response to diverse stresses. The ISR is initiated when any 1 of 4 stress-sensing kinases (protein kinase R-like endoplasmic reticulum kinase [PERK], general control non-derepressible 2 [GCN2], double-stranded RNA-dependent protein kinase [PKR], heme-regulated eukaryotic translation initiation factor 2α kinase [HRI]) becomes activated to phosphorylate the protein translation initiation factor eukaryotic translation initiation factor 2α (eIF2α), shifting gene expression toward a comprehensive rewiring of cellular machinery to promote adaptation. Although the ISR has been shown to play an important role in the homeostasis of multiple tissues, evidence suggests that it is particularly crucial for the development and ongoing health of the pancreas. Among the most synthetically dynamic tissues in the body, the exocrine and endocrine pancreas relies heavily on the ISR to rapidly adjust cell function to meet the metabolic demands of the organism. The hardwiring of the ISR into normal pancreatic functions and adaptation to stress may explain why it is a commonly used pro-oncogenic and therapy-resistance mechanism in pancreatic ductal adenocarcinoma and pancreatic neuroendocrine tumors. Here, we review what is known about the key roles that the ISR plays in the development, homeostasis, and neoplasia of the pancreas.
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Affiliation(s)
- Greg Malnassy
- Department of Pathology, University of Chicago, Chicago, Illinois
| | - Leah Ziolkowski
- The Ben May Department for Cancer Research, University of Chicago, Chicago, Illinoi; Committee on Molecular Metabolism and Nutrition, University of Chicago, Chicago, Illinois
| | - Kay F Macleod
- The Ben May Department for Cancer Research, University of Chicago, Chicago, Illinoi; Committee on Molecular Metabolism and Nutrition, University of Chicago, Chicago, Illinois; Committee on Cancer Biology, University of Chicago, Chicago, Illinois.
| | - Scott A Oakes
- Department of Pathology, University of Chicago, Chicago, Illinois; Committee on Molecular Metabolism and Nutrition, University of Chicago, Chicago, Illinois; Committee on Cancer Biology, University of Chicago, Chicago, Illinois.
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15
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Yasrab M, Rizk RC, Lopez-Ramirez F, Ahmed TM, Blanco A, Javed AA, Chu LC, Fishman EK, Kawamoto S. Diminishing calcifications as a potential predictor of pancreatic ductal adenocarcinoma arising in association with IPMN in patients with chronic pancreatitis. Radiol Case Rep 2024; 19:5299-5303. [PMID: 39280750 PMCID: PMC11399793 DOI: 10.1016/j.radcr.2024.08.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 08/03/2024] [Accepted: 08/05/2024] [Indexed: 09/18/2024] Open
Abstract
Chronic pancreatitis (CP) is a progressive benign fibroinflammatory condition involving repeated episodes of pancreatic inflammation, which lead to fibrotic tissue replacement and subsequent pancreatic insufficiency. A lifetime risk of developing pancreatic ductal adenocarcinoma (PDAC) in patients with chronic pancreatitis is reported to be 1.5%-4%. However, diagnosis of PDAC in patients with CP can be challenging, in part due to overlapping imaging features. In rare instances, pancreatic parenchymal calcifications that are typically associated with chronic pancreatitis may diminish in the case of a developing PDAC. In this article, we present a patient with chronic pancreatitis in whom calcifications decreased at the time of pancreatic ductal adenocarcinoma diagnosis, as compared to prior CT imaging. The unique imaging features of "diminishing calcifications" associated with a hypoattenuating lesion can potentially be a useful sign of pancreatic ductal adenocarcinoma and may aid in early diagnosis and prompt treatment intervention.
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Affiliation(s)
- Mohammad Yasrab
- Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ryan C Rizk
- Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Felipe Lopez-Ramirez
- Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Taha M Ahmed
- Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Alejandra Blanco
- Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ammar A Javed
- Department of Surgery, New York University Langone Hospital, New York, NY, USA
| | - Linda C Chu
- Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Elliot K Fishman
- Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Satomi Kawamoto
- Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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16
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Solil D, Dite P, Senkyrik M, Bojkova M, Kianicka B. Acute pancreatitis as a risk factor of chronic pancreatitis and pancreatic cancer. An overview. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2024; 168:284-287. [PMID: 39254152 DOI: 10.5507/bp.2024.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 06/28/2024] [Indexed: 09/11/2024] Open
Abstract
This is an overview of relation between acute and chronic pancreatitis and between acute pancreatitis and pancreatic cancer. Acute pancreatitis and recurrent acute pancreatitis are an etiological factor of chronic pancreatitis. Population-based studies have calculated the risk of acute recurrent pancreatitis after the first attack of acute pancreatitis to be 20% and development of chronic pancreatitis after first attack of acute pancreatitis is 10%. An important risk factor is tobacco smoking. Acute and chronic pancreatitis are risk factors for pancreatic cancer. The risk of acute pancreatitis is related to the number of recurrences of acute pancreatitis, but not the etiology of acute pancreatitis. Acute pancreatitis, as well as chronic pancreatitis, are risk factors for pancreatic cancer. After an attack of acute pancreatitis or recurrent acute pancreatitis a patient should be regarded as a high risk.
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Affiliation(s)
- David Solil
- Department of Gastroenterology and Internal Medicine, University Hospital Brno and Faculty of Medicine, Masaryk University Brno, Brno, Czech Republic
| | - Petr Dite
- Department of Gastroenterology and Internal Medicine, University Hospital Brno and Faculty of Medicine, Masaryk University Brno, Brno, Czech Republic
- Department of Clinic Subjects, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
| | - Michal Senkyrik
- Department of Gastroenterology and Internal Medicine, University Hospital Brno and Faculty of Medicine, Masaryk University Brno, Brno, Czech Republic
| | - Martina Bojkova
- Department of Internal Medicine, University Hospital Ostrava, Ostrava, Czech Republic
| | - Bohuslav Kianicka
- 2nd Department of Internal Medicine, St. Anne's University Hospital Brno and Faculty of Medicine, Masaryk University Brno, Brno, Czech Republic
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17
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Leal AS, Liby KT. The BRD4 Inhibitor I-BET-762 Reduces HO-1 Expression in Macrophages and the Pancreas of Mice. Int J Mol Sci 2024; 25:9985. [PMID: 39337472 PMCID: PMC11432103 DOI: 10.3390/ijms25189985] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 09/10/2024] [Accepted: 09/12/2024] [Indexed: 09/30/2024] Open
Abstract
In pancreatic cancer, the tumor microenvironment (TME) accounts for up to 90% of the tumor mass. Pancreatitis, characterized by the increased infiltration of macrophages into the pancreas, is a known risk factor for pancreatic cancer. The NRF2 (nuclear factor erythroid 2-related factor 2) transcription factor regulates responses to oxidative stress and can promote cancer and chemoresistance. NRF2 also attenuates inflammation through the regulation of macrophage-specific genes. Heme oxygenase 1 (HO-1) is expressed by anti-inflammatory macrophages to degrade heme, and its expression is dependent on NRF2 translocation to the nucleus. In macrophages stimulated with conditioned media from pancreatic cancer cells, HO-1 protein levels increased, which correlated with higher NRF2 expression in the nuclear fraction. Significant differences in macrophage infiltration and HO-1 expression were detected in LSL-KrasG12D/+; Pdx-1-Cre (KC) mice, Nrf2 whole-body knockout (KO) mice and wildtype mice with pancreatitis. Since epigenetic modulation is a mechanism used by tumors to regulate the TME, using small molecules as epigenetic modulators to activate immune recognition is therapeutically desirable. When the bromodomain inhibitor I-BET-762 was used to treat macrophages or mice with pancreatitis, high levels of HO-1 were reduced. This study shows that bromodomain inhibitors can be used to prevent physiological responses to inflammation that promote tumorigenesis.
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Affiliation(s)
- Ana S. Leal
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
| | - Karen T. Liby
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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18
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Oberstein PE, Dias Costa A, Kawaler EA, Cardot-Ruffino V, Rahma OE, Beri N, Singh H, Abrams TA, Biller LH, Cleary JM, Enzinger P, Huffman BM, McCleary NJ, Perez KJ, Rubinson DA, Schlechter BL, Surana R, Yurgelun MB, Wang SJ, Remland J, Brais LK, Bollenrucher N, Chang E, Ali LR, Lenehan PJ, Dolgalev I, Werba G, Lima C, Keheler CE, Sullivan KM, Dougan M, Hajdu C, Dajee M, Pelletier MR, Nazeer S, Squires M, Bar-Sagi D, Wolpin BM, Nowak JA, Simeone DM, Dougan SK. Blockade of IL1β and PD1 with Combination Chemotherapy Reduces Systemic Myeloid Suppression in Metastatic Pancreatic Cancer with Heterogeneous Effects in the Tumor. Cancer Immunol Res 2024; 12:1221-1235. [PMID: 38990554 PMCID: PMC11369625 DOI: 10.1158/2326-6066.cir-23-1073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 05/15/2024] [Accepted: 07/10/2024] [Indexed: 07/12/2024]
Abstract
Innate inflammation promotes tumor development, although the role of innate inflammatory cytokines in established human tumors is unclear. Herein, we report clinical and translational results from a phase Ib trial testing whether IL1β blockade in human pancreatic cancer would alleviate myeloid immunosuppression and reveal antitumor T-cell responses to PD1 blockade. Patients with treatment-naïve advanced pancreatic ductal adenocarcinoma (n = 10) were treated with canakinumab, a high-affinity monoclonal human antiinterleukin-1β (IL1β), the PD1 blocking antibody spartalizumab, and gemcitabine/n(ab)paclitaxel. Analysis of paired peripheral blood from patients in the trial versus patients receiving multiagent chemotherapy showed a modest increase in HLA-DR+CD38+ activated CD8+ T cells and a decrease in circulating monocytic myeloid-derived suppressor cells (MDSC) by flow cytometry for patients in the trial but not in controls. Similarly, we used patient serum to differentiate monocytic MDSCs in vitro and showed that functional inhibition of T-cell proliferation was reduced when using on-treatment serum samples from patients in the trial but not when using serum from patients treated with chemotherapy alone. Within the tumor, we observed few changes in suppressive myeloid-cell populations or activated T cells as assessed by single-cell transcriptional profiling or multiplex immunofluorescence, although increases in CD8+ T cells suggest that improvements in the tumor immune microenvironment might be revealed by a larger study. Overall, the data indicate that exposure to PD1 and IL1β blockade induced a modest reactivation of peripheral CD8+ T cells and decreased circulating monocytic MDSCs; however, these changes did not lead to similarly uniform alterations in the tumor microenvironment.
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Affiliation(s)
- Paul E. Oberstein
- Department of Medicine, NYU Langone Health, New York, New York.
- Perlmutter Cancer Center, NYU Langone Health, New York, New York.
| | - Andressa Dias Costa
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
| | - Emily A. Kawaler
- Perlmutter Cancer Center, NYU Langone Health, New York, New York.
- Department of Surgery, NYU Langone Health, New York, New York.
| | - Victoire Cardot-Ruffino
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts.
- Department of Immunology, Harvard Medical School, Boston, Massachusetts.
| | - Osama E. Rahma
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts.
| | - Nina Beri
- Department of Medicine, NYU Langone Health, New York, New York.
- Perlmutter Cancer Center, NYU Langone Health, New York, New York.
| | - Harshabad Singh
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts.
| | - Thomas A. Abrams
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts.
| | - Leah H. Biller
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts.
| | - James M. Cleary
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts.
| | - Peter Enzinger
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts.
| | - Brandon M. Huffman
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts.
| | - Nadine J. McCleary
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts.
| | - Kimberly J. Perez
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts.
| | - Douglas A. Rubinson
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts.
| | - Benjamin L. Schlechter
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts.
| | - Rishi Surana
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts.
| | - Matthew B. Yurgelun
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts.
| | - S. Jennifer Wang
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts.
| | - Joshua Remland
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
| | - Lauren K. Brais
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
| | - Naima Bollenrucher
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts.
| | - Eugena Chang
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts.
| | - Lestat R. Ali
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts.
- Department of Immunology, Harvard Medical School, Boston, Massachusetts.
- Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
| | - Patrick J. Lenehan
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts.
- Department of Immunology, Harvard Medical School, Boston, Massachusetts.
| | - Igor Dolgalev
- Department of Medicine, NYU Langone Health, New York, New York.
- Perlmutter Cancer Center, NYU Langone Health, New York, New York.
| | - Gregor Werba
- Perlmutter Cancer Center, NYU Langone Health, New York, New York.
- Department of Surgery, NYU Langone Health, New York, New York.
| | - Cibelle Lima
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
| | - C. Elizabeth Keheler
- Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
| | - Keri M. Sullivan
- Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
| | - Michael Dougan
- Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
| | - Cristina Hajdu
- Perlmutter Cancer Center, NYU Langone Health, New York, New York.
- Department of Pathology, NYU Langone Health, New York, New York.
| | - Maya Dajee
- Novartis Institute for Biomedical Research, Cambridge, Massachusetts.
| | - Marc R. Pelletier
- Novartis Institute for Biomedical Research, Cambridge, Massachusetts.
| | | | | | - Dafna Bar-Sagi
- Department of Medicine, NYU Langone Health, New York, New York.
- Perlmutter Cancer Center, NYU Langone Health, New York, New York.
| | - Brian M. Wolpin
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts.
| | - Jonathan A. Nowak
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
- Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts.
| | - Diane M. Simeone
- Perlmutter Cancer Center, NYU Langone Health, New York, New York.
- Department of Surgery, NYU Langone Health, New York, New York.
| | - Stephanie K. Dougan
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts.
- Department of Immunology, Harvard Medical School, Boston, Massachusetts.
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19
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Tandan M, Pal P, Jagtap N, Reddy DN. Endoscopic interventions in pancreatic strictures and stones-A structured approach. Indian J Gastroenterol 2024:10.1007/s12664-024-01644-9. [PMID: 39145851 DOI: 10.1007/s12664-024-01644-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Accepted: 06/25/2024] [Indexed: 08/16/2024]
Abstract
Chronic pancreatitis (CP) is an irreversible disease of varied etiology characterized by destruction of pancreatic tissue and loss of both exocrine and endocrine function. Pain is the dominant and most common presenting symptom. The common cause for pain in CP is ductal hypertension due to obstruction of the flow of pancreatic juice in the main pancreatic duct either due to stones or stricture or a combination of both. With advances in technology and techniques, endoscopic retrograde cholangiography (ERCP) and stenting should be the first line of therapy for strictures of the main pancreatic duct (MPD). Small calculi in the MPD can be extracted by ERCP and balloon trawl. Extracorporeal shockwave lithotripsy (ESWL) remains the standard of care for large pancreatic calculi and aims to fragment the stones 3 mm or less that can easily be extracted by a subsequent ERCP. Single operator pancreatoscopy with intraductal lithotripsy is a technique in evolution and can be tried when ESWL is not available or is unsuccessful in producing stone fragmentation.
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Affiliation(s)
- Manu Tandan
- Medical Gastroenterology, Asian Institute of Gastroenterology, Somajiguda, 6-3-661, Hyderabad, 500 082, India.
| | - Partha Pal
- Medical Gastroenterology, Asian Institute of Gastroenterology, Somajiguda, 6-3-661, Hyderabad, 500 082, India
| | - Nitin Jagtap
- Medical Gastroenterology, Asian Institute of Gastroenterology, Somajiguda, 6-3-661, Hyderabad, 500 082, India
| | - D Nageshwar Reddy
- Medical Gastroenterology, Asian Institute of Gastroenterology, Somajiguda, 6-3-661, Hyderabad, 500 082, India
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20
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Treekitkarnmongkol W, Dai J, Liu S, Sankaran D, Nguyen T, Balasenthil S, Hurd MW, Chen M, Katayama H, Roy-Chowdhuri S, Calin GA, Brand RE, Lampe PD, Hu TY, Maitra A, Koay EJ, Killary AM, Sen S. Blood-Based microRNA Biomarker Signature of Early-Stage Pancreatic Ductal Adenocarcinoma With Lead-Time Trajectory in Prediagnostic Samples. GASTRO HEP ADVANCES 2024; 3:1098-1115. [PMID: 39529638 PMCID: PMC11550741 DOI: 10.1016/j.gastha.2024.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 08/02/2024] [Indexed: 11/16/2024]
Abstract
Background and Aims Clinically validated biomarker of pancreatic ductal adenocarcinoma (PDAC), carbohydrate antigen 19-9 (CA19-9), has limited sensitivity and specificity for early-stage disease. Circulating miRNAs in plasma associated with cancer relevant pathways were developed as early detection biomarkers. Methods 2083 miRNAs in 15 μl of plasma from multicenter age-matched cohorts (N = 203: healthy controls, n = 46; pancreatitis controls, n = 36; diagnosed cases: n = 121) and a prediagnostic Prostate, Lung, Colorectal, and Ovarian age- and gender-matched cohort (N = 96; controls, n = 48; prediagnosed cases, n = 48) were interrogated. A three-miRNA biomarker signature was developed for early-stage PDAC. Results The three-miRNA signature (let-7i-5p, miR-130a-3p and miR-221-3p) detected PDAC from healthy controls independently (area under the curve [AUC] of stage I, II, I-IV = 0.970, 0.975, 0.974) and in combination with CA19-9 (AUC of stage I, II, I-IV = 1.000, 0.992, 0.995). It also discriminated chronic pancreatitis (AUC of stage I, II, I-IV = 0.932, 0.931, 0.929), improving performance of CA19-9 alone (AUC of stage I, II, I-IV = 0.763, 0.701, 0.735) in combination (AUC of stage I, II, I-IV = 0.971, 0.943, 0.951). Blinded validation in prediagnostic Prostate, Lung, Colorectal, and Ovarian cohort revealed lead-time trajectory increase in AUC from 0.702 to 0.729 to 0.757 at twelve-, six-, and three-months before PDAC diagnosis, respectively. The signature also helped stratification of patients with different circulating tumor DNA and imaging subtypes. Conclusion Plasma miRNAs associated with oncogenic pathways may serve as PDAC early detection biomarkers.
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Affiliation(s)
- Warapen Treekitkarnmongkol
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jianliang Dai
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Suyu Liu
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Deivendran Sankaran
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Tristian Nguyen
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Seetharaman Balasenthil
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Mark W. Hurd
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
- Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Meng Chen
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Hiroshi Katayama
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Sinchita Roy-Chowdhuri
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - George A. Calin
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Randall E. Brand
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Paul D. Lampe
- Translation Research Program, Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, Washington
| | - Tony Y. Hu
- Department of Molecular & Cellular Biology, Center for Cellular and Molecular Diagnostics, Tulane University School of Medicine, New Orleans, Louisiana
| | - Anirban Maitra
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
- Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Eugene J. Koay
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ann M. Killary
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Subrata Sen
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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21
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Saeki K, Wood IS, Wang WCK, Patil S, Sun Y, Schaeffer DF, Su GH, Kopp JL. Acvr1b Loss Increases Formation of Pancreatic Precancerous Lesions From Acinar and Ductal Cells of Origin. Cell Mol Gastroenterol Hepatol 2024; 18:101387. [PMID: 39111635 PMCID: PMC11404226 DOI: 10.1016/j.jcmgh.2024.101387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 07/25/2024] [Accepted: 07/30/2024] [Indexed: 08/27/2024]
Abstract
BACKGROUND & AIMS Pancreatic ductal adenocarcinoma can develop from precursor lesions, including pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasm (IPMN). Previous studies indicated that loss of Acvr1b accelerates the Kras-mediated development of papillary IPMN in the mouse pancreas; however, the cell type predominantly affected by these genetic changes remains unclear. METHODS We investigated the contribution of cellular origin by inducing IPMN associated mutations (KRASG12D expression and Acvr1b loss) specifically in acinar (Ptf1aCreER;KrasLSL-G12D;Acvr1bfl/fl mice) or ductal (Sox9CreER;KrasLSL-G12D;Acvr1bfl/fl mice) cells in mice. We then performed magnetic resonance imaging and a thorough histopathologic analysis of their pancreatic tissues. RESULTS The loss of Acvr1b increased the development of pancreatic intraepithelial neoplasia and IPMN-like lesions when either acinar or ductal cells expressed a Kras mutation. Magnetic resonance imaging, immunohistochemistry, and histology revealed large IPMN-like lesions in these mice that exhibited features of flat, gastric epithelium. In addition, cyst formation in both mouse models was accompanied by chronic pancreatitis. Experimental acute pancreatitis accelerated the development of large mucinous cysts and pancreatic intraepithelial neoplasia when acinar, but not ductal, cells expressed mutant Kras and lost Acvr1b. CONCLUSIONS These findings indicate that loss of Acvr1b in the presence of the Kras oncogene promotes the development of large and small precancerous lesions from both ductal and acinar cells. However, the IPMN-like phenotype was not equivalent to that observed when these mutations were made in all pancreatic cells during development. Our study underscores the significance of the cellular context in the initiation and progression of precursor lesions from exocrine cells.
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Affiliation(s)
- Kiyoshi Saeki
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York; Department of Otolaryngology and Head and Neck Surgery, Columbia University Irving Medical Center, New York, New York
| | - Ian S Wood
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, Canada
| | - Wei Chuan Kevin Wang
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, Canada
| | - Shilpa Patil
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, Canada
| | - Yanping Sun
- Oncology Precision Therapeutics and Imaging Core (OPTIC), Columbia University Medical Center, New York, New York
| | - David F Schaeffer
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
| | - Gloria H Su
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York; Department of Otolaryngology and Head and Neck Surgery, Columbia University Irving Medical Center, New York, New York
| | - Janel L Kopp
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, Canada.
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22
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Chen Z, Wang Z, Bao H, Ma S. Gut microbiota and pancreatic cancer risk, and the mediating role of immune cells and inflammatory cytokines: a Mendelian randomization study. Front Immunol 2024; 15:1408770. [PMID: 39119339 PMCID: PMC11306078 DOI: 10.3389/fimmu.2024.1408770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Accepted: 07/12/2024] [Indexed: 08/10/2024] Open
Abstract
Introduction Gut microbiota (GM) influences the occurrence and development of pancreatic cancer (PC), potentially through the involvement of inflammatory cytokines (IC) and immune cells (IM). We aimed to investigate the causal impact of the gut microbiota (GM) on pancreatic cancer (PC) and identify potential IC and IM mediators. Methods The summary statistics data from whole-genome association studies of gut microbiota, immune cells, inflammatory cytokines, and four types of pancreatic tumors (MNP: Malignant neoplasm of pancreas; BNP: Benign neoplasm of pancreas; ADCP: Adenocarcinoma and ductal carcinoma of pancreas; NTCP: Neuroendocrine tumor and carcinoma of pancreas). Two-sample univariable Mendelian randomization (UVMR), multivariable Mendelian randomization (MVMR), and mediation analysis were employed to assess the causal relationship between gut microbiota (GM) and pancreatic cancer (PC), as well as potential IC and IM mediators. Results The two-sample UVMR analysis showed causal relationships between 20 gut microbiota species and pancreatic cancer, with pancreatic cancer affecting the abundance of 37 gut microbiota species. Mediation analysis revealed that Interleukin-6 (IL-6), "CD4 on naive CD4+ T cell" and "SSC-A on HLA DR+ Natural Killer" mediated the causal effects of gut microbiota on pancreatic cancer. Conclusion This Mendelian randomization study demonstrates causal relationships between several specific gut microbiota and pancreatic cancer, as well as potential mediators (IC, IM).
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Affiliation(s)
- Zhiting Chen
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhe Wang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Hejing Bao
- Department of Oncology, Panyu Central Hospital, Guangzhou, China
| | - Shudong Ma
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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23
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Pliszka M, Szablewski L. Associations between Diabetes Mellitus and Selected Cancers. Int J Mol Sci 2024; 25:7476. [PMID: 39000583 PMCID: PMC11242587 DOI: 10.3390/ijms25137476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 06/15/2024] [Accepted: 06/24/2024] [Indexed: 07/16/2024] Open
Abstract
Cancer is one of the major causes of mortality and is the second leading cause of death. Diabetes mellitus is a serious and growing problem worldwide, and its prevalence continues to grow; it is the 12th leading cause of death. An association between diabetes mellitus and cancer has been suggested for more than 100 years. Diabetes is a common disease diagnosed among patients with cancer, and evidence indicates that approximately 8-18% of patients with cancer have diabetes, with investigations suggesting an association between diabetes and some particular cancers, increasing the risk for developing cancers such as pancreatic, liver, colon, breast, stomach, and a few others. Breast and colorectal cancers have increased from 20% to 30% and there is a 97% increased risk of intrahepatic cholangiocarcinoma or endometrial cancer. On the other hand, a number of cancers and cancer therapies increase the risk of diabetes mellitus. Complications due to diabetes in patients with cancer may influence the choice of cancer therapy. Unfortunately, the mechanisms of the associations between diabetes mellitus and cancer are still unknown. The aim of this review is to summarize the association of diabetes mellitus with selected cancers and update the evidence on the underlying mechanisms of this association.
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Affiliation(s)
- Monika Pliszka
- Chair and Department of General Biology and Parasitology, Medical University of Warsaw, Chałubińskiego Str. 5, 02-004 Warsaw, Poland
| | - Leszek Szablewski
- Chair and Department of General Biology and Parasitology, Medical University of Warsaw, Chałubińskiego Str. 5, 02-004 Warsaw, Poland
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24
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Mahadevan KK, Dyevoich AM, Chen Y, Li B, Sugimoto H, Sockwell AM, McAndrews KM, Sthanam LK, Wang H, Shalapour S, Watowich SS, Kalluri R. Type I conventional dendritic cells facilitate immunotherapy in pancreatic cancer. Science 2024; 384:eadh4567. [PMID: 38935717 PMCID: PMC11841451 DOI: 10.1126/science.adh4567] [Citation(s) in RCA: 18] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Accepted: 04/23/2024] [Indexed: 06/29/2024]
Abstract
Inflammation and tissue damage associated with pancreatitis can precede or occur concurrently with pancreatic ductal adenocarcinoma (PDAC). We demonstrate that in PDAC coupled with pancreatitis (ptPDAC), antigen-presenting type I conventional dendritic cells (cDC1s) are specifically activated. Immune checkpoint blockade therapy (iCBT) leads to cytotoxic CD8+ T cell activation and elimination of ptPDAC with restoration of life span even upon PDAC rechallenge. Using PDAC antigen-loaded cDC1s as a vaccine, immunotherapy-resistant PDAC was rendered sensitive to iCBT with elimination of tumors. cDC1 vaccination coupled with iCBT identified specific CDR3 sequences in the tumor-infiltrating CD8+ T cells with potential therapeutic importance. This study identifies a fundamental difference in the immune microenvironment in PDAC concurrent with, or without, pancreatitis and provides a rationale for combining cDC1 vaccination with iCBT as a potential treatment option.
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Affiliation(s)
- Krishnan K. Mahadevan
- Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Allison M. Dyevoich
- Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Yang Chen
- Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Bingrui Li
- Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Hikaru Sugimoto
- Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Amari M. Sockwell
- Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Kathleen M. McAndrews
- Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Lakshmi Kavitha Sthanam
- Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Huamin Wang
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Shabnam Shalapour
- Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Stephanie S. Watowich
- Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Raghu Kalluri
- Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX
- Department of Bioengineering, Rice University, Houston, TX
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
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25
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Molero X, Ayuso JR, Balsells J, Boadas J, Busquets J, Casteràs A, Concepción M, Cuatrecasas M, Fernàndez Esparrach G, Fort E, Garcia Borobia F, Ginès À, Ilzarbe L, Loras C, Masachs M, Merino X, Olsina JJ, Puig-Diví V, Salord S, Serrano T, Vaquero EC. Chronic pancreatitis for the clinician: complications and special forms of the disease. Interdisciplinary position paper of the Catalan Society of Digestology (SCD) and the Catalan Pancreatic Society (SCPanc). Minerva Gastroenterol (Torino) 2024; 70:208-224. [PMID: 35262306 DOI: 10.23736/s2724-5985.22.03127-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Chronic pancreatitis tends to develop a number of complications that may constitute the form of presentation of the disease. Some societies have issued guidelines for diagnosis and treatment of chronic pancreatitis complications, but the level of evidence for any topic is usually low and recommendations tend to be weak. We aimed to provide defined position statements for the clinician based on updated review of published literature and on multidisciplinary expert agreement. The goal was to propose defined terminology and rational diagnostic/therapeutic circuits based on current knowledge. To this end 14 sections related to complications and special forms of chronic pancreatitis (early chronic, groove and autoimmune pancreatitis) were reviewed by 21 specialists from 6 different fields to generate 32 statements. Featured statements assert common bile duct stenosis does not require invasive treatment (endoscopic or surgical) unless cholestasis, cholangitis, lithiasis or other symptoms develop. Pancreatic duct strictures and calculi should be approached (after ruling out malignancy) if causing pain, pancreatitis, pseudocysts or other complications. Treatment of symptomatic pseudocysts must be individualized, considering associated main duct stenosis, vascular and pericystic complications. Higher risk conditions for pancreatic cancer are advance age, smoking, genetic background, recent diagnosis of chronic pancreatitis or diabetes, and appearance of new symptoms. Groove pancreatitis can initially be treated with conservative measures. Both prednisolone or rituximab can induce remission and maintenance of autoimmune pancreatitis. Internal fistula, vascular complications, bacterial overgrowth, osteoporosis and renal lithiasis require specific therapeutic approaches.
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Affiliation(s)
- Xavier Molero
- Unit of Exocrine Pancreas Research, Department of Gastroenterology, VHIR, CIBERehd, Vall d'Hebron University Hospital, Autonomous University of Barcelona, Barcelona, Spain -
| | - Juan R Ayuso
- Department of Radiology, CDI, IDIBAPS, Hospital Clínic Barcelona, Barcelona, Spain
| | - Joaquim Balsells
- Department of Hepato-Pancreato-Biliary and Transplantation Surgery, University Hospital Vall d'Hebron, Barcelona, Spain
| | - Jaume Boadas
- Department of Gastroenterology, Consorci Sanitari de Terrassa, Terrassa, Spain
| | - Juli Busquets
- Department of Hepatobiliary and Pancreatic Surgery, IDIBELL, Bellvitge University Hospital, University of Barcelona, L'Hospitalet de Llobregat, Spain
| | - Anna Casteràs
- Unit of Diabetes and Metabolism Research, VHIR, Vall d'Hebron University Hospital, Autonomous University of Barcelona, Barcelona, Spain
| | - Mar Concepción
- Department of Gastroenterology, Santa Creu i Sant Pau Hospital, Autonomous University of Barcelona, Barcelona, Spain
| | - Míriam Cuatrecasas
- Department of Pathology, CIBEREHD, IDIBAPS, Hospital Clínic Barcelona, University of Barcelona, Barcelona, Spain
| | - Gloria Fernàndez Esparrach
- Unit of Endoscopy, Department of Gastroenterology, CIBEREHD IDIBAPS, Hospital Clínic Barcelona, University of Barcelona, Barcelona, Spain
| | - Esther Fort
- Department of Gastroenterology, Doctor Josep Trueta University Hospital, Girona, Spain
| | | | - Àngels Ginès
- Unit of Endoscopy, Department of Gastroenterology, CIBEREHD IDIBAPS, Hospital Clínic Barcelona, University of Barcelona, Barcelona, Spain
| | - Lucas Ilzarbe
- Department of Gastroenterology, Hospital del Mar Parc Salut Mar, Barcelona, Spain
| | - Carme Loras
- Department of Gastroenterology, CIBERehd, University of Barcelona, Terrassa, Spain
| | - Miquel Masachs
- Department of Endocopy, Vall d'Hebron University Hospital, Autonomous University of Barcelona, Terrassa, Spain
| | - Xavier Merino
- Department of Radiodiagnostic, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Jorge J Olsina
- Department of General Surgery, Institute for Research in Biomedicine of Lleida (IRBLleida), University Hospital Arnau de Vilanova, Lleida, Spain
| | - Valentí Puig-Diví
- Department of Gastroenterology, Parc Taulí Research and Innovation Institute I3PT, Parc Taulí University Hospital, Sabadell, Spain
| | - Sílvia Salord
- Unit of Hepato-Bilio-Pancreatic, Department of Digestive Diseases, IDIBELL, Bellvitge University Hospital, University of Barcelona, L'Hospitalet de Llobregat, Spain
| | - Teresa Serrano
- Department of Pathology, IDIBELL, CIBERehd, Bellvitge University Hospital, L'Hospitalet de Llobregat, Spain
| | - Eva C Vaquero
- Department of Gastroenterology, CIBEREHD IDIBAPS, Hospital Clínic Barcelona, University of Barcelona, Barcelona, Spain
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26
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Matsumoto T, Tanaka G, Mori S, Niki M, Sato S, Shiraki T, Iso Y, Nagashima K, Irisawa A, Nozawa Y, Takada-Owada A, Ishida K, Aoki T. A resected case of pancreatic head cancer developing 40 years after lateral pancreaticojejunostomy for chronic pancreatitis. Clin J Gastroenterol 2024; 17:537-542. [PMID: 38396137 PMCID: PMC11127812 DOI: 10.1007/s12328-024-01924-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 01/11/2024] [Indexed: 02/25/2024]
Abstract
A 72-year-old male patient presented to our department complaining of with upper abdominal pain and jaundice. He had a history of a side-to-side pancreaticojejunostomy performed 40 years previously for chronic pancreatitis. A diagnostic workup revealed a tumor 3 cm in size in the pancreatic head as the etiology of the jaundice. Subsequently, the patient was diagnosed with resectable pancreatic cancer. Following two cycles of neoadjuvant chemotherapy, an extended pancreatoduodenectomy was performed because of tumor invasion at the previous pancreaticojejunostomy site. Concurrent portal vein resection and reconstruction were performed. Pathological examination confirmed invasive ductal carcinoma (T2N1M0, Stage IIB). This case highlights the clinical challenges in pancreatic head carcinoma following a side-to-side pancreaticojejunostomy. Although pancreaticojejunostomy is believed to reduce the risk of pancreatic cancer in patients with chronic pancreatitis, clinicians should be aware that, even after this surgery, there is still a chance of developing pancreatic cancer during long-term follow-up.
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Affiliation(s)
- Takatsugu Matsumoto
- Department of Hepato-Biliary-Pancreatic Surgery, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Tochigi, 321-0293, Japan.
| | - Genki Tanaka
- Department of Hepato-Biliary-Pancreatic Surgery, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Tochigi, 321-0293, Japan
| | - Shozo Mori
- Department of Hepato-Biliary-Pancreatic Surgery, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Tochigi, 321-0293, Japan
| | - Maiko Niki
- Department of Hepato-Biliary-Pancreatic Surgery, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Tochigi, 321-0293, Japan
| | - Shun Sato
- Department of Hepato-Biliary-Pancreatic Surgery, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Tochigi, 321-0293, Japan
| | - Takayuki Shiraki
- Department of Hepato-Biliary-Pancreatic Surgery, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Tochigi, 321-0293, Japan
| | - Yukihiro Iso
- Department of Hepato-Biliary-Pancreatic Surgery, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Tochigi, 321-0293, Japan
| | - Kazunori Nagashima
- Department of Gastroenterology, Dokkyo Medical University, Mibu, Tochigi, Japan
| | - Atsushi Irisawa
- Department of Gastroenterology, Dokkyo Medical University, Mibu, Tochigi, Japan
| | - Yumi Nozawa
- Department of Diagnostic Pathology, Dokkyo Medical University, Mibu, Tochigi, Japan
| | - Atsuko Takada-Owada
- Department of Diagnostic Pathology, Dokkyo Medical University, Mibu, Tochigi, Japan
| | - Kazuyuki Ishida
- Department of Diagnostic Pathology, Dokkyo Medical University, Mibu, Tochigi, Japan
| | - Taku Aoki
- Department of Hepato-Biliary-Pancreatic Surgery, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Tochigi, 321-0293, Japan
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27
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Morishima N, Kamada Y, Ota H, Iwagami Y, Takahashi H, Shimosaka M, Sakon D, Kondo J, Yamada M, Kumada T, Eguchi H, Miyoshi E. Serum levels of the N-terminal fragment of connective tissue growth factor is a novel biomarker for chronic pancreatitis. Pract Lab Med 2024; 40:e00402. [PMID: 38828385 PMCID: PMC11143898 DOI: 10.1016/j.plabm.2024.e00402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Accepted: 05/16/2024] [Indexed: 06/05/2024] Open
Abstract
Chronic inflammation of the pancreas is considered to be one of the causes of pancreatic cancer. However, the diagnosis of chronic pancreatitis (CP) is very difficult in the pancreas, where biopsies are difficult to perform. The prevalence of CP is estimated to be many times more common than in patients with actual symptomatic CP. In recent years, abnormal cleavage of certain proteins has attracted attention as a biomarker for CP other than pancreatic enzymes. Connective tissue growth factor (CTGF) is one of the growth factors involved in tissue repair and other processes and is increased by stimulation of transforming growth factor-β, suggesting a relationship of CTGF with fibrosis. In this study, we measured the total length of CTGF in blood and N-terminal fragment CTGF in 48 cases of chronic pancreatitis, 64 cases of pancreatic cancer and 45 healthy volunteers (HV). Interestingly, we found that blood N-terminal fragment CTGF level was significantly increased in CP and pancreatic cancer patients. Multiple logistic regression analysis showed serum levels of N-terminal fragment CTGF, CRP and amylase were significant and independent variables for the differential diagnosis of CP from HV. Receiver operating characteristic analysis showed that area under the curve (AUC) value of serum N-terminal fragment CTGF level was 0.933, which can differentiate between CP and HV. Several factors would be involved in the increase in serum N-terminal fragment CTGF level. In conclusion, serum N-terminal fragment CTGF level is a promising new biomarker for CP.
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Affiliation(s)
- Naoki Morishima
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Yoshihiro Kamada
- Department of Advanced Metabolic Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Hiyori Ota
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Yoshifumi Iwagami
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Hidenori Takahashi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Munefumi Shimosaka
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan
| | - Daisuke Sakon
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Jumpei Kondo
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | | | - Takashi Kumada
- Department of Nursing, Faculty of Nursing, Gifu Kyoritsu University, 5-50, Kitagata-cho, Ogaki, 503-8550, Gifu, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Eiji Miyoshi
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
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Swanton C, Bernard E, Abbosh C, André F, Auwerx J, Balmain A, Bar-Sagi D, Bernards R, Bullman S, DeGregori J, Elliott C, Erez A, Evan G, Febbraio MA, Hidalgo A, Jamal-Hanjani M, Joyce JA, Kaiser M, Lamia K, Locasale JW, Loi S, Malanchi I, Merad M, Musgrave K, Patel KJ, Quezada S, Wargo JA, Weeraratna A, White E, Winkler F, Wood JN, Vousden KH, Hanahan D. Embracing cancer complexity: Hallmarks of systemic disease. Cell 2024; 187:1589-1616. [PMID: 38552609 PMCID: PMC12077170 DOI: 10.1016/j.cell.2024.02.009] [Citation(s) in RCA: 73] [Impact Index Per Article: 73.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 01/25/2024] [Accepted: 02/08/2024] [Indexed: 04/02/2024]
Abstract
The last 50 years have witnessed extraordinary developments in understanding mechanisms of carcinogenesis, synthesized as the hallmarks of cancer. Despite this logical framework, our understanding of the molecular basis of systemic manifestations and the underlying causes of cancer-related death remains incomplete. Looking forward, elucidating how tumors interact with distant organs and how multifaceted environmental and physiological parameters impinge on tumors and their hosts will be crucial for advances in preventing and more effectively treating human cancers. In this perspective, we discuss complexities of cancer as a systemic disease, including tumor initiation and promotion, tumor micro- and immune macro-environments, aging, metabolism and obesity, cancer cachexia, circadian rhythms, nervous system interactions, tumor-related thrombosis, and the microbiome. Model systems incorporating human genetic variation will be essential to decipher the mechanistic basis of these phenomena and unravel gene-environment interactions, providing a modern synthesis of molecular oncology that is primed to prevent cancers and improve patient quality of life and cancer outcomes.
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Affiliation(s)
- Charles Swanton
- The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK.
| | - Elsa Bernard
- The Francis Crick Institute, London, UK; INSERM U981, Gustave Roussy, Villejuif, France
| | | | - Fabrice André
- INSERM U981, Gustave Roussy, Villejuif, France; Department of Medical Oncology, Gustave Roussy, Villejuif, France; Paris Saclay University, Kremlin-Bicetre, France
| | - Johan Auwerx
- Laboratory of Integrative Systems Physiology, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland
| | - Allan Balmain
- UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA
| | | | - René Bernards
- Division of Molecular Carcinogenesis, Oncode Institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Susan Bullman
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - James DeGregori
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | | | - Ayelet Erez
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Gerard Evan
- The Francis Crick Institute, London, UK; Kings College London, London, UK
| | - Mark A Febbraio
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
| | - Andrés Hidalgo
- Department of Immunobiology, Yale University, New Haven, CT 06519, USA; Area of Cardiovascular Regeneration, Centro Nacional de Investigaciones Cardiovasculares, 28029 Madrid, Spain
| | - Mariam Jamal-Hanjani
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
| | - Johanna A Joyce
- Department of Oncology, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland
| | | | - Katja Lamia
- Department of Molecular Medicine, Scripps Research Institute, La Jolla, CA, USA
| | - Jason W Locasale
- Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA; Department of Molecular and Structural Biochemistry, North Carolina State University, Raleigh, NC, USA
| | - Sherene Loi
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; The Sir Department of Medical Oncology, The University of Melbourne, Parkville, VIC, Australia
| | | | - Miriam Merad
- Department of immunology and immunotherapy, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Kathryn Musgrave
- Translational and Clinical Research Institute, Newcastle University, Newcastle, UK; Department of Haematology, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Ketan J Patel
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Sergio Quezada
- Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK
| | - Jennifer A Wargo
- Department of Surgical Oncology, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ashani Weeraratna
- Sidney Kimmel Cancer Center, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Eileen White
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA; Ludwig Princeton Branch, Ludwig Institute for Cancer Research, Princeton, NJ, USA
| | - Frank Winkler
- Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Neuro-oncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - John N Wood
- Molecular Nociception Group, WIBR, University College London, London, UK
| | | | - Douglas Hanahan
- Lausanne Branch, Ludwig Institute for Cancer Research, Lausanne, Switzerland; Swiss institute for Experimental Cancer Research (ISREC), EPFL, Lausanne, Switzerland; Agora Translational Cancer Research Center, Lausanne, Switzerland.
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Kurita Y, Kubota K, Fujita Y, Tsujino S, Sekino Y, Kasuga N, Iwasaki A, Iwase M, Izuka T, Kagawa K, Tanida E, Yagi S, Hasegawa S, Sato T, Hosono K, Kobayashi N, Ichikawa Y, Nakajima A, Endo I. IgG4-related pancreatobiliary diseases could be associated with onset of pancreatobiliary cancer: A multicenter cohort study. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2024; 31:173-182. [PMID: 38124014 DOI: 10.1002/jhbp.1404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 10/30/2023] [Accepted: 11/10/2023] [Indexed: 12/23/2023]
Abstract
BACKGROUND The risk and prognosis of pancreatobiliary cancer and in patients with autoimmune pancreatitis (AIP) and IgG4-related sclerosing cholangitis (IgG4-SC) remain unclear. Therefore, we retrospectively investigated the risk of pancreatobiliary cancer and prognosis in patients with AIP and IgG4-SC. METHODS Patients with AIP and IgG4-SC at seven centers between 1998 and 2022 were investigated. The following data were evaluated: (1) the number of cancers diagnosed and standardized incidence ratio (SIR) for pancreatobiliary and other cancers during the observational period and (2) prognosis after diagnosis of AIP and IgG4-SC using standardized mortality ratio (SMR). RESULTS This study included 201 patients with AIP and IgG4-SC. The mean follow-up period was 5.7 years. Seven cases of pancreatic cancer were diagnosed, and the SIR was 8.11 (95% confidence interval [CI]: 7.29-9.13). Three cases of bile duct cancer were diagnosed, and the SIR was 6.89 (95% CI: 6.20-7.75). The SMR after the diagnosis of AIP and IgG4-SC in cases that developed pancreatobiliary cancer were 4.03 (95% CI: 2.83-6.99). CONCLUSIONS Patients with autoimmune pancreatitis and IgG4-SC were associated with a high risk of pancreatic and bile duct cancer. Patients with AIP and IgG4-SC have a worse prognosis when they develop pancreatobiliary cancer.
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Affiliation(s)
- Yusuke Kurita
- Department of Gastroenterology and Hepatology, Yokohama City University Hospital, Yokohama, Japan
| | - Kensuke Kubota
- Department of Gastroenterology and Hepatology, Yokohama City University Hospital, Yokohama, Japan
| | - Yuji Fujita
- Department of Hepato-Biliary-Pancreatic Medicine, NTT Medical Center Tokyo, Tokyo, Japan
| | - Seitaro Tsujino
- Department of Hepato-Biliary-Pancreatic Medicine, NTT Medical Center Tokyo, Tokyo, Japan
| | - Yusuke Sekino
- Department of Gastroenterology, Yokohama Rosai Hospital, Yokohama, Japan
| | - Noriki Kasuga
- Department of Gastroenterology, Yokohama Rosai Hospital, Yokohama, Japan
| | - Akito Iwasaki
- Department of Gastroenterology, Yokohama Sakae Kyosai Hospital, Yokohama, Japan
| | - Mai Iwase
- Department of Gastroenterology, Hiratsuka City Hospital, Hiratsuka, Japan
| | - Takeshi Izuka
- Department of Gastroenterology, Hiratsuka City Hospital, Hiratsuka, Japan
| | - Koichi Kagawa
- Department of Gastroenterology, Keiyu Hospital, Yokohama, Japan
| | - Emiko Tanida
- Department of Gastroenterology, Machida Municipal Hospital, Tokyo, Japan
| | - Shin Yagi
- Department of Gastroenterology and Hepatology, Yokohama City University Hospital, Yokohama, Japan
| | - Sho Hasegawa
- Department of Gastroenterology and Hepatology, Yokohama City University Hospital, Yokohama, Japan
| | - Takamitsu Sato
- Department of Gastroenterology and Hepatology, Yokohama City University Hospital, Yokohama, Japan
| | - Kunihiro Hosono
- Department of Gastroenterology and Hepatology, Yokohama City University Hospital, Yokohama, Japan
| | | | - Yasushi Ichikawa
- Department of Oncology, Yokohama City University Hospital, Yokohama, Japan
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University Hospital, Yokohama, Japan
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Hospital, Yokohama, Japan
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Joseph AM, Al Aiyan A, Al-Ramadi B, Singh SK, Kishore U. Innate and adaptive immune-directed tumour microenvironment in pancreatic ductal adenocarcinoma. Front Immunol 2024; 15:1323198. [PMID: 38384463 PMCID: PMC10879611 DOI: 10.3389/fimmu.2024.1323198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 01/11/2024] [Indexed: 02/23/2024] Open
Abstract
One of the most deadly and aggressive cancers in the world, pancreatic ductal adenocarcinoma (PDAC), typically manifests at an advanced stage. PDAC is becoming more common, and by the year 2030, it is expected to overtake lung cancer as the second greatest cause of cancer-related death. The poor prognosis can be attributed to a number of factors, including difficulties in early identification, a poor probability of curative radical resection, limited response to chemotherapy and radiotherapy, and its immunotherapy resistance. Furthermore, an extensive desmoplastic stroma that surrounds PDAC forms a mechanical barrier that prevents vascularization and promotes poor immune cell penetration. Phenotypic heterogeneity, drug resistance, and immunosuppressive tumor microenvironment are the main causes of PDAC aggressiveness. There is a complex and dynamic interaction between tumor cells in PDAC with stromal cells within the tumour immune microenvironment. The immune suppressive microenvironment that promotes PDAC aggressiveness is contributed by a range of cellular and humoral factors, which itself are modulated by the cancer. In this review, we describe the role of innate and adaptive immune cells, complex tumor microenvironment in PDAC, humoral factors, innate immune-mediated therapeutic advances, and recent clinical trials in PDAC.
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Affiliation(s)
- Ann Mary Joseph
- Department of Veterinary Medicine (CAVM), United Arab Emirates University, Al Ain, United Arab Emirates
| | - Ahmad Al Aiyan
- Department of Veterinary Medicine (CAVM), United Arab Emirates University, Al Ain, United Arab Emirates
| | - Basel Al-Ramadi
- Department of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
- Zayed Center for Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Shiv K. Singh
- Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center, Goettingen, Germany
| | - Uday Kishore
- Department of Veterinary Medicine (CAVM), United Arab Emirates University, Al Ain, United Arab Emirates
- Zayed Center for Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
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Mohanan A, Biju P, V B, V G. Unraveling Proto-Oncogene (ErbB2) Expression in Patients With Carcinoma Head of Pancreas and Chronic Pancreatitis Patients: A Case-Control Study. Cureus 2024; 16:e54859. [PMID: 38533139 PMCID: PMC10964396 DOI: 10.7759/cureus.54859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/25/2024] [Indexed: 03/28/2024] Open
Abstract
Background The pre-malignant tendency of the normal, non-affected portion of the pancreas is not as well explored as the multicentricity documented in pancreatic cancer cases. In order to ascertain the expression of inflammatory markers and Erythroblastic Oncogene B (ErbB2) in the non-affected pancreas in patients with pancreatic cancer, a case-control study was carried out. Materials and methods In patients who underwent pancreatoduodenectomy for pancreatic cancer (PC), pro-inflammatory genes and a tumor marker, erythroblastic oncogene 2 (ErbB2) in the epidermal growth factor receptor family were analyzed in the pancreatic tissue at the cut surface of the normal pancreas using qRT-PCR. Twenty patients diagnosed with Chronic pancreatitis (CP) after Frey's surgical procedure were selected, and their pancreatic tissues were analyzed as controls. The HPLC-purified primers were designed using National Center for Biotechnology Information (NCBI) software. The primer's specificity was verified for gene expression analysis using the Basic Local Alignment Search Tool (BLAST). The genes under study were normalized using β-actin as the housekeeping gene, and the 2-ddct method was used to compute the fold change compared to the control sample. Results Patients with margin-positive were not included. Pro-inflammatory genes (TNF-α, NF-kβ, and COX-2) had significantly lower foldchange in PC patients compared to the CP group. The CP control group had higher levels of IL-6 gene expression than the PC group. Patients with pancreatic cancer had a considerably higher expression of the ErbB2 gene than patients with CP. Conclusion The upregulated ErbB2 gene in the unaffected pancreatic tissue of pancreatic cancer patients, when compared to controls, indicates that the remaining pancreas may have the capacity to cause cancer. Proto-oncogene may play a role in the pathophysiologic process in patients with pancreatic cancer.
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Affiliation(s)
- Abhina Mohanan
- Surgical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education & Research, Puducherry, IND
| | - Pottakkat Biju
- Surgical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education & Research, Puducherry, IND
| | - Balasubramaniyan V
- Biochemistry, Jawaharlal Institute of Postgraduate Medical Education & Research, Puducherry, IND
| | - Gladwin V
- Anatomy, Jawaharlal Institute of Postgraduate Medical Education & Research, Puducherry, IND
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Madela F, Ferndale L, Aldous C. Diagnostic Differentiation between Pancreatitis and Pancreatic Cancer: A Scoping Review. Diagnostics (Basel) 2024; 14:290. [PMID: 38337806 PMCID: PMC10855106 DOI: 10.3390/diagnostics14030290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 01/25/2024] [Accepted: 01/26/2024] [Indexed: 02/12/2024] Open
Abstract
Pancreatitis, encompassing acute and chronic forms, and pancreatic cancer pose significant challenges to the exocrine tissue of the pancreas. Recurrence rates and complications following acute pancreatitis episodes can lead to long-term risks, including diabetes mellitus. Chronic pancreatitis can develop in approximately 15% of cases, regardless of the initial episode's severity. Alcohol-induced pancreatitis, idiopathic causes, cigarette smoking, and hereditary pancreatitis contribute to the progression to chronic pancreatitis. Chronic pancreatitis is associated with an increased risk of pancreatic cancer, with older age at onset and smoking identified as risk factors. This scoping review aims to synthesise recent publications (2017-2022) on the diagnostic differentiation between pancreatitis and pancreatic cancer while identifying knowledge gaps in the field. The review focuses on biomarkers and imaging techniques in individuals with pancreatitis and pancreatic cancer. Promising biomarkers such as faecal elastase-1 and specific chemokines offer non-invasive ways to assess pancreatic insufficiency and detect early biomarkers for chronic pancreatitis. Imaging techniques, including computed tomography (CT), magnetic resonance imaging (MRI), endoscopic ultrasound (EUS), and positron emission tomography (PET), aid in differentiating between chronic pancreatitis and pancreatic cancer. However, accurately distinguishing between the two conditions remains a challenge, particularly when a mass is present in the head of the pancreas. Several knowledge gaps persist despite advancements in understanding the association between pancreatitis and pancreatic cancer, including the correlation between histopathological grading systems, non-invasive imaging techniques, and biomarkers in chronic pancreatitis to determine the risk of progression to pancreatic cancer, as well as differentiating between the two conditions. Further research is necessary to enhance our understanding of these aspects, which can ultimately improve the diagnosis and management of pancreatitis and pancreatic cancer.
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Affiliation(s)
- Fusi Madela
- Department of Surgery, School of Clinical Medicine, College of Health Sciences, University of KwaZulu-Natal, Durban 4000, South Africa; (L.F.)
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Jeong SH, Hurh K, Park EC, Leigh JH, Kim SH, Jang SI. Risk of Pancreatic Cancer After Acute Pancreatitis: A Retrospective Analysis of the Korean National Sample Cohort. J Korean Med Sci 2024; 39:e21. [PMID: 38288535 PMCID: PMC10825454 DOI: 10.3346/jkms.2024.39.e21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Accepted: 11/22/2023] [Indexed: 02/01/2024] Open
Abstract
BACKGROUND Acute pancreatitis may increase the risk of pancreatic cancer, although this association remains unclear. Therefore, we aimed to investigate this association. METHODS We retrospectively analyzed the 2002-2019 Korean National Health Insurance Service-National Sample Cohort using 1:3 propensity score matching for sex and age (acute pancreatitis, n = 4,494; matched controls, n = 13,482). We calculated the hazard ratio (HR) for pancreatic cancer risk in patients with acute pancreatitis using Cox proportional hazards regression. RESULTS Acute pancreatitis was significantly associated with an increased risk of pancreatic cancer throughout the study period (adjusted HR, 7.56 [95% confidence interval, 5.00-11.41]), which persisted for 2, 2-5, and > 5 years post-diagnosis (19.11 [9.60-38.05], 3.46 [1.35-8.33], and 2.73 [1.21-6.15], respectively). This pancreatitis-related pancreatic cancer risk became insignificant beyond 10 years of follow-up (1.24 [0.24-6.49]). Furthermore, this risk notably increased as the number of recurrent acute pancreatitis episodes increased (1 episode: 5.25 [3.31-8.33], 2 episodes: 11.35 [6.38-20.19], ≥ 3 episodes: 24.58 [13.66-44.26]). CONCLUSION Following an acute pancreatitis diagnosis, the risk of pancreatic cancer increases significantly in the initial years, with a rapid increase further accentuated with recurrent acute pancreatitis episodes. Additional study is needed to evaluate whether this increased risk of carcinogenesis is attributed to accumulated inflammation.
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Affiliation(s)
- Sung Hoon Jeong
- Department of Rehabilitation Medicine, Seoul National University Hospital, Seoul, Korea
- Institute of Health Services Research, Yonsei University, Seoul, Korea
- Department of Rehabilitation Medicine, National Traffic Injury Rehabilitation Hospital, Yangpyeong, Korea
| | - Kyungduk Hurh
- Institute of Health Services Research, Yonsei University, Seoul, Korea
- Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Eun-Cheol Park
- Institute of Health Services Research, Yonsei University, Seoul, Korea
- Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Ja-Ho Leigh
- Department of Rehabilitation Medicine, Seoul National University Hospital, Seoul, Korea
- Department of Rehabilitation Medicine, National Traffic Injury Rehabilitation Hospital, Yangpyeong, Korea
| | - Seung Hoon Kim
- Institute of Health Services Research, Yonsei University, Seoul, Korea
- Department of Preventive Medicine, Eulji University School of Medicine, Daejeon, Korea.
| | - Sung-In Jang
- Institute of Health Services Research, Yonsei University, Seoul, Korea
- Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Korea.
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Pateras IS, Igea A, Nikas IP, Leventakou D, Koufopoulos NI, Ieronimaki AI, Bergonzini A, Ryu HS, Chatzigeorgiou A, Frisan T, Kittas C, Panayiotides IG. Diagnostic Challenges during Inflammation and Cancer: Current Biomarkers and Future Perspectives in Navigating through the Minefield of Reactive versus Dysplastic and Cancerous Lesions in the Digestive System. Int J Mol Sci 2024; 25:1251. [PMID: 38279253 PMCID: PMC10816510 DOI: 10.3390/ijms25021251] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 01/12/2024] [Accepted: 01/16/2024] [Indexed: 01/28/2024] Open
Abstract
In the setting of pronounced inflammation, changes in the epithelium may overlap with neoplasia, often rendering it impossible to establish a diagnosis with certainty in daily clinical practice. Here, we discuss the underlying molecular mechanisms driving tissue response during persistent inflammatory signaling along with the potential association with cancer in the gastrointestinal tract, pancreas, extrahepatic bile ducts, and liver. We highlight the histopathological challenges encountered in the diagnosis of chronic inflammation in routine practice and pinpoint tissue-based biomarkers that could complement morphology to differentiate reactive from dysplastic or cancerous lesions. We refer to the advantages and limitations of existing biomarkers employing immunohistochemistry and point to promising new markers, including the generation of novel antibodies targeting mutant proteins, miRNAs, and array assays. Advancements in experimental models, including mouse and 3D models, have improved our understanding of tissue response. The integration of digital pathology along with artificial intelligence may also complement routine visual inspections. Navigating through tissue responses in various chronic inflammatory contexts will help us develop novel and reliable biomarkers that will improve diagnostic decisions and ultimately patient treatment.
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Affiliation(s)
- Ioannis S. Pateras
- 2nd Department of Pathology, “Attikon” University Hospital, Medical School, National and Kapodistrian University of Athens, 124 62 Athens, Greece; (D.L.); (N.I.K.); (A.I.I.); (I.G.P.)
| | - Ana Igea
- Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain;
- Mobile Genomes, Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela (USC), 15706 Santiago de Compostela, Spain
| | - Ilias P. Nikas
- Medical School, University of Cyprus, 2029 Nicosia, Cyprus
| | - Danai Leventakou
- 2nd Department of Pathology, “Attikon” University Hospital, Medical School, National and Kapodistrian University of Athens, 124 62 Athens, Greece; (D.L.); (N.I.K.); (A.I.I.); (I.G.P.)
| | - Nektarios I. Koufopoulos
- 2nd Department of Pathology, “Attikon” University Hospital, Medical School, National and Kapodistrian University of Athens, 124 62 Athens, Greece; (D.L.); (N.I.K.); (A.I.I.); (I.G.P.)
| | - Argyro Ioanna Ieronimaki
- 2nd Department of Pathology, “Attikon” University Hospital, Medical School, National and Kapodistrian University of Athens, 124 62 Athens, Greece; (D.L.); (N.I.K.); (A.I.I.); (I.G.P.)
| | - Anna Bergonzini
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Alfred Nobels Allé 8, 141 52 Stockholm, Sweden;
- Department of Molecular Biology and Umeå Centre for Microbial Research (UCMR), Umeå University, 901 87 Umeå, Sweden;
| | - Han Suk Ryu
- Department of Pathology, Seoul National University Hospital, Seoul 03080, Republic of Korea;
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 115 27 Athens, Greece;
| | - Teresa Frisan
- Department of Molecular Biology and Umeå Centre for Microbial Research (UCMR), Umeå University, 901 87 Umeå, Sweden;
| | - Christos Kittas
- Department of Histopathology, Biomedicine Group of Health Company, 156 26 Athens, Greece;
| | - Ioannis G. Panayiotides
- 2nd Department of Pathology, “Attikon” University Hospital, Medical School, National and Kapodistrian University of Athens, 124 62 Athens, Greece; (D.L.); (N.I.K.); (A.I.I.); (I.G.P.)
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Amerifar M, Arabnozari H, Shokrzadeh M, Habibi E. Evaluation of antioxidant properties and cytotoxicity of brown algae (nizamuddinia zanardinii) in uterine (hela) and pancreatic cancer cell lines (paca-2). Hum Exp Toxicol 2024; 43:9603271241227228. [PMID: 38238028 DOI: 10.1177/09603271241227228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2024]
Abstract
INTRODUCTION Pancreatic cancer and cervical cancer are among the most common cancers. Brown algae have anti-inflammatory, anti-cancer, anti-fungal, antioxidant, and immune-boosting properties. This study investigated the antioxidant properties and the effect of brown algae extract on pancreatic and uterine cancer cells. MATERIALS AND METHODS In this study, Cervical (Hela) and pancreas (Paca-2) cancer cell lines were examined. The algae materials were extracted by sequential maceration method and amount of fucoxanthin content in the sample was determined by using High Performance Liquid Chromatography (HPLC) system. The cytotoxic effect of different concentrations of brown algae was measured by the MTT assay. All statistical calculations for comparing IC50 were analyzed using Graph Pad Prism software. RESULTS the algal sample contained an average of 102.52 ± 0.12 μg of fucoxanthin per 100 g. IC50 for 2, 2-diphenyl-1-picrylhydrazyl (DPPH) and hydrogen peroxide free radical scavenging activity for methanolic extract was 2.02 and 11.98 ± 0.13 respectively. Brown algae in all fractions inhibited cell growth and survival. In Hela cell lines, the methanolic extract was the most effective inhibitor, while in Paca cell lines, hexane and methanolic extracts were particularly potent. The methanolic extract was more toxic than other fractions on Hela and Paca cell lines. CONCLUSION This study highlights brown algae extracts strong anticancer effects on uterine and pancreatic cancer cells, suggesting its potential as a natural anticancer drug. Different fractions of the extract showed superior apoptotic and cytotoxic effects, with higher concentrations leading to increased apoptotic effects and reduced survival rates of cancer cells.
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Affiliation(s)
- Milad Amerifar
- Student Research Committee, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Hesamoddin Arabnozari
- Student Research Committee, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Mohammad Shokrzadeh
- Pharmaceutical Sciences Research Center, Hemoglobinopathy Institute, Mazandaran University of Medical Sciences, Sari, Iran
| | - Emran Habibi
- Medicinal Plants Research Center, Mazandaran University of Medical Sciences, Sari, Iran
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Akahoshi K, Kanno A, Miwata T, Nagai H, Yokoyama K, Ikeda E, Ando K, Tamada K, Fukushima N, Lefor AK, Yamamoto H. Cholangiocarcinoma Resembling IgG4-related Sclerosing Cholangitis. Intern Med 2023; 62:3495-3500. [PMID: 37081688 PMCID: PMC10749809 DOI: 10.2169/internalmedicine.1144-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 03/07/2023] [Indexed: 04/22/2023] Open
Abstract
A 66-year-old man diagnosed with immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) with diffuse intrahepatic bile duct stenosis and elevated serum IgG4 levels was referred for a further examination because of elevated serum carbohydrate antigen 19-9 levels despite treatment with corticosteroids. An umbilical nodule was found on a physical examination and a biopsy showed adenocarcinoma. Although several imaging studies revealed no changes from prior studies, bile cytology collected by endoscopic retrograde cholangiopancreatography showed adenocarcinoma. Consequently, the patient was diagnosed with cholangiocarcinoma resembling IgG4-SC after detecting an umbilical metastasis, also known as Sister Mary Joseph's nodule.
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Affiliation(s)
- Kazuaki Akahoshi
- Department of Medicine, Division of Gastroenterology, Jichi Medical University, Japan
| | - Atsushi Kanno
- Department of Medicine, Division of Gastroenterology, Jichi Medical University, Japan
| | - Tetsurou Miwata
- Department of Medicine, Division of Gastroenterology, Jichi Medical University, Japan
| | - Hiroki Nagai
- Department of Medicine, Division of Gastroenterology, Jichi Medical University, Japan
| | - Kensuke Yokoyama
- Department of Medicine, Division of Gastroenterology, Jichi Medical University, Japan
| | - Eriko Ikeda
- Department of Medicine, Division of Gastroenterology, Jichi Medical University, Japan
| | - Kozue Ando
- Department of Medicine, Division of Gastroenterology, Jichi Medical University, Japan
| | - Kiichi Tamada
- Department of Medicine, Division of Gastroenterology, Jichi Medical University, Japan
| | | | | | - Hironori Yamamoto
- Department of Medicine, Division of Gastroenterology, Jichi Medical University, Japan
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37
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Mahapatra SJ, Garg PK. The Power of Population Cohorts and Modeling: Pancreatitis-A Case in Point. Gastroenterology 2023; 165:1329-1333. [PMID: 37806459 DOI: 10.1053/j.gastro.2023.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 10/01/2023] [Indexed: 10/10/2023]
Affiliation(s)
| | - Pramod Kumar Garg
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India.
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38
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Khan E, Chakrabarty S, Shariff S, Bardhan M. Genetics and Genomics of Chronic Pancreatitis with a Focus on Disease Biology and Molecular Pathogenesis. Glob Med Genet 2023; 10:324-334. [PMID: 38025192 PMCID: PMC10665123 DOI: 10.1055/s-0043-1776981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2023] Open
Abstract
Chronic pancreatitis is a long-term fibroinflammatory condition of the pancreas with varying incidences across countries. The recent increase in its occurrence implies the involvement of genetic, hereditary, and unconventional risk factors. However, there is a lack of updated literature on recent advances in genetic polymorphisms of chronic pancreatitis. Therefore, this review aims to present recent findings on the genetic implications of chronic pancreatitis based on individual gene mechanisms and to discuss epigenetics and epistasis involved in the disease. Four mechanisms have been implicated in the pathogenesis of chronic pancreatitis, including premature activation of proteases, endoplasmic reticulum stress, ductal pathway dysfunction, and inflammatory pathway dysfunction. These mechanisms involve genes such as PRSS1, PRSS2, SPINK, CEL, PNLIP, PNLIPRP2, CFTR, CaSR, CLDN2, Alpha 1 antitrypsin, and GGT1 . Studying genetic polymorphisms on the basis of altered genes and their products may aid clinicians in identifying predispositions in patients with and without common risk factors. Further research may also identify associations between genetic predispositions and disease staging or prognosis, leading to personalized treatment protocols and precision medicine.
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Affiliation(s)
- Erum Khan
- Department of Neurology, Alzheimer's Disease Research Center, The university of Alabama at Birmingham, Birmingham, United States
| | - Soura Chakrabarty
- Department of Pathology, University of Cambridge, Cambridge, United Kingdom
| | | | - Mainak Bardhan
- Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, Florida, United States
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Park SM, Kim KB, Han JH, Kim N, Kang TU, Swan H, Kim HJ. Incidence and risk of pancreatic cancer in patients with acute or chronic pancreatitis: a population-based cohort study. Sci Rep 2023; 13:18930. [PMID: 37919344 PMCID: PMC10622573 DOI: 10.1038/s41598-023-45382-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Accepted: 10/18/2023] [Indexed: 11/04/2023] Open
Abstract
We aimed to evaluate the incidence and risk of pancreatic cancer (PC) in pancreatitis. We identified patients with acute pancreatitis (AP) (n = 225,811, 50.0%) and chronic pancreatitis (CP) (n = 225,685, 50.0%) from Korean population-based data and matched them with age- and sex-matched controls (n = 4,514,960). We analyzed the incidence and adjusted hazard ratios (aHRs) of PC among patients followed for more than 2 years or 5 years, and assessed risk changes over time in single episode of AP (SAP), recurrent AP (RAP), CP with AP, and CP without AP groups. We also performed subgroup analysis for both sexes. The incidences (per 104 person-years) and risks (aHR) of PC were higher in the RAP (12.69, 5.00) or CP with AP (12.12, 5.74) groups compared to the SAP (2.31, 1.32) or CP without AP (2.28, 1.57) groups. The risks of PC decreased over time, however, the risk of PC remained elevated in the RAP and CP with AP groups for more than 8 years. Females with RAP, SAP, and CP with AP had higher risks of PC than males. The risk of PC is higher and persists for longer duration in patients with RAP and CP with AP compared to those with SAP or CP without AP.
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Affiliation(s)
- Seon Mee Park
- Department of Internal Medicine, Chungbuk National University College of Medicine, Cheongju, Republic of Korea
- Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Republic of Korea
| | - Ki Bae Kim
- Department of Internal Medicine, Chungbuk National University College of Medicine, Cheongju, Republic of Korea
- Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Republic of Korea
| | - Joung-Ho Han
- Department of Internal Medicine, Chungbuk National University College of Medicine, Cheongju, Republic of Korea
- Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Republic of Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seungnam, Republic of Korea
| | - Tae Uk Kang
- Health and Wellness College, Sungshin Women's University, Seoul, Republic of Korea
| | - Heather Swan
- Department of Preventive Medicine, Korea University College of Medicine, 126-1, 5-ga, Inchon-ro, Seoul, 136-705, Republic of Korea
| | - Hyun Jung Kim
- Department of Preventive Medicine, Korea University College of Medicine, 126-1, 5-ga, Inchon-ro, Seoul, 136-705, Republic of Korea.
- Department of Public Health, Graduate School, Korea University, Seoul, Republic of Korea.
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40
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Roos-Mattila M, Kaprio T, Mustonen H, Hagström J, Saharinen P, Haglund C, Seppänen H. The possible dual role of Ang-2 in the prognosis of pancreatic cancer. Sci Rep 2023; 13:18725. [PMID: 37907568 PMCID: PMC10618172 DOI: 10.1038/s41598-023-45194-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 10/17/2023] [Indexed: 11/02/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) features a dense desmoplastic stroma, which raises the intratumoral interstitial pressure leading to vascular collapse and hypoxia, inducing angiogenesis. Vascular growth factors, such as vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2), increase in PDAC. A high VEGF and a high circulating Ang-2 associate with shorter survival in PDAC. In addition to the circulatory Ang-2, PDAC endothelial and epithelial cells express Ang-2. No correlation between tumor epithelial nor endothelial cell Ang-2 expression and survival has been published. We aimed to examine Ang-2 expression and survival. This study comprised PDAC surgical patients at Helsinki University Hospital in 2000-2013. Ang-2 immunohistochemistry staining was completed on 168 PDAC patient samples. Circulating Ang-2 levels were measured using ELISA in the sera of 196 patients. Ang-2 levels were assessed against clinical data and patient outcomes. A low tumor epithelial Ang-2 expression predicted shorter disease-specific survival (DSS) compared with a high expression (p = 0.003). A high serum Ang-2 associated with shorter DSS compared with a low circulating Ang-2 (p = 0.016). Ang-2 seemingly plays a dual role in PDAC survival. Further studies are needed to determine the mechanisms causing tumor cell Ang-2 expression and its positive association with survival.
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Affiliation(s)
- Matilda Roos-Mattila
- Department of Surgery, Helsinki University Hospital, Helsinki, Finland
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- iCAN, Digital Cancer Precision Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Tuomas Kaprio
- Department of Surgery, Helsinki University Hospital, Helsinki, Finland.
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
- iCAN, Digital Cancer Precision Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
- Department of Pathology, Haartmaninkatu 3 (PB 21), University of Helsinki, 00014, Helsinki, Finland.
| | - Harri Mustonen
- Department of Surgery, Helsinki University Hospital, Helsinki, Finland
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- iCAN, Digital Cancer Precision Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Jaana Hagström
- Department of Surgery, Helsinki University Hospital, Helsinki, Finland
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- iCAN, Digital Cancer Precision Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Department of Oral Pathology and Radiology, University of Turku, Turku, Finland
| | - Pipsa Saharinen
- Wihuri Research Institute, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- iCAN, Digital Cancer Precision Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Caj Haglund
- Department of Surgery, Helsinki University Hospital, Helsinki, Finland
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- iCAN, Digital Cancer Precision Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Hanna Seppänen
- Department of Surgery, Helsinki University Hospital, Helsinki, Finland
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- iCAN, Digital Cancer Precision Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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Rho S, Martin S, Nigogosyan Z, Kushnir V, Mintz AJ, Hu ZI. Pancreatic tail cancer in the setting of pancreatitis with a review of the literature: A case report. Clin Case Rep 2023; 11:e8023. [PMID: 37830064 PMCID: PMC10565090 DOI: 10.1002/ccr3.8023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 08/26/2023] [Accepted: 09/25/2023] [Indexed: 10/14/2023] Open
Abstract
Environmental risk factors for pancreatic cancer include acute and chronic pancreatitis, obesity, and tobacco use. Differentiating a pancreatic neoplasm in a patient with pancreatitis can be challenging due to their similar presentations. A 57-year-old African American man with a history of congestive heart failure, pancreatitis, and incomplete pancreas divisum presented with an epigastric abdominal pain that radiated to his back. Imaging showed necrotizing pancreatitis, a developing splenic infarct, and a mass at the pancreas tail. The patient was discharged with pain medications and was recommended follow-up imaging after resolution of his pancreatitis. He was readmitted to the emergency department 2 weeks later with recurrent acute abdominal pain. Computed tomography scan of abdomen and pelvis followed by magnetic resonance imaging and endoscopic ultrasound revealed an infiltrative pancreatic tail mass. Biopsy of the mass confirmed a locally advanced pancreatic tail adenocarcinoma. Chronic pancreatitis is associated with pancreatic cancer. Practitioners should be aware of the co-existence of chronic pancreatitis and pancreatic cancer, and the initial steps to evaluate a malignancy in chronic pancreatitis.
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Affiliation(s)
- Shinji Rho
- School of MedicineWashington University School of MedicineSt. LouisMissouriUSA
| | - Sooyoung Martin
- Department of RadiologyWashington University School of MedicineSt. LouisMissouriUSA
| | - Zack Nigogosyan
- Department of RadiologyWashington University School of MedicineSt. LouisMissouriUSA
| | - Vladimir Kushnir
- Department of GastroenterologyWashington University School of MedicineSt. LouisMissouriUSA
| | - Aaron J. Mintz
- Department of RadiologyWashington University School of MedicineSt. LouisMissouriUSA
| | - Zishuo Ian Hu
- Department of Medicine, Division of Oncology, Section of Medical OncologyWashington University School of MedicineSt. LouisMissouriUSA
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Lopez K, Deng JJ, Xu Y, Sharkey FE, Wang P, Liu J. Exploring the Role of YAP1 and TAZ in Pancreatic Acinar Cells and the Therapeutic Potential of VT-104 in Pancreatic Inflammation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.09.18.558321. [PMID: 37781601 PMCID: PMC10541090 DOI: 10.1101/2023.09.18.558321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/03/2023]
Abstract
Increasing evidences have linked the hippo pathway with the fibroinflammatory diseases. We generated a series of genetic knockout mice for targeting the key components of Hippo pathway to examine the individual effects of YAP1 and TAZ on pancreatic inflammation and evaluated the therapeutic potential of the YAP1/TAZ inhibitor VT-104. Mice with acinar-specific knockout of YAP1/TAZ did not exhibit any histological abnormalities in the pancreas. LATS1/2 deficiency induced acinar-to-ductal metaplasia, immune cell infiltration and fibroblast activation, which were rescued by the homozygous knockout YAP1, but not TAZ. Additionally, treatment with VT-104 also decreased pathological alterations induced by deletions of LATS1 and LATS2 in acinar cells. Our findings highlight the critical role of YAP1 in modulating pancreatic inflammation and demonstrate that VT-104 holds therapeutic potential to mitigate pancreatitis-associated pathological manifestations. Further exploration is necessary to unravel the underlying mechanisms and translate these insights into clinical applications.
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43
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Koltai T. Earlier Diagnosis of Pancreatic Cancer: Is It Possible? Cancers (Basel) 2023; 15:4430. [PMID: 37760400 PMCID: PMC10526520 DOI: 10.3390/cancers15184430] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 07/31/2023] [Accepted: 08/06/2023] [Indexed: 09/29/2023] Open
Abstract
Pancreatic ductal adenocarcinoma has a very high mortality rate which has been only minimally improved in the last 30 years. This high mortality is closely related to late diagnosis, which is usually made when the tumor is large and has extensively infiltrated neighboring tissues or distant metastases are already present. This is a paradoxical situation for a tumor that requires nearly 15 years to develop since the first founding mutation. Response to chemotherapy under such late circumstances is poor, resistance is frequent, and prolongation of survival is almost negligible. Early surgery has been, and still is, the only approach with a slightly better outcome. Unfortunately, the relapse percentage after surgery is still very high. In fact, early surgery clearly requires early diagnosis. Despite all the advances in diagnostic methods, the available tools for improving these results are scarce. Serum tumor markers permit a late diagnosis, but their contribution to an improved therapeutic result is very limited. On the other hand, effective screening methods for high-risk populations have not been fully developed as yet. This paper discusses the difficulties of early diagnosis, evaluates whether the available diagnostic tools are adequate, and proposes some simple and not-so-simple measures to improve it.
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Affiliation(s)
- Tomas Koltai
- Hospital del Centro Gallego de Buenos Aires, Buenos Aires C1094, Argentina
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44
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Kawakami Y, Koshita S, Kanno Y, Ogawa T, Kusunose H, Sakai T, Yonamine K, Miyamoto K, Kozakai F, Okada T, Oikawa M, Tsuchiya T, Noda Y, Sawai T, Nakase H, Ito K. Pancreatic ductal adenocarcinomas concomitant with intraductal papillary mucinous neoplasms of the pancreas: A investigation of those clinicopathological features by analyzing 48 patients who underwent surgery for those lesions. Pancreatology 2023; 23:674-681. [PMID: 37604732 DOI: 10.1016/j.pan.2023.07.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 07/26/2023] [Accepted: 07/31/2023] [Indexed: 08/23/2023]
Abstract
BACKGROUND Differences between pancreatic ductal adenocarcinomas (PDACs) concomitant with intraductal papillary mucinous neoplasm (IPMN) (C-PDACs), those without IPMN (NC-PDACs) and invasive cancers derived from IPMN (IC-Ds) have not been fully clarified. METHODS Forty-eight patients with C-PDAC were included to investigate the differences in 1) clinicopathological features and 2) post-operative courses among the three invasive cancer groups. RESULTS 1) Characteristics of C-PDACs were mostly similar to those of NC-PDACs; whereas, between C-PDACs and IC-Ds, the rate of mucinous carcinoma (2%/25%, p = 0.003) and pathological stage (IA, 15%/36%, p = 0.033; III, 31%/4%, p = 0.015) significantly differed. Most C-PDACs coexisted with small, multifocal IPMNs without mural nodules. 2) Cumulative 5-year recurrence-free survival (RFS) rate related to extra-pancreatic recurrence was significantly worse in C-PDACs than in IC-Ds (35%/69%, p = 0.008) and was not significantly different between C-PDACs and NC-PDACs (35%/18%). This related to intra-pancreatic recurrence tended to be poor in the order of IC-Ds, C-PDACs, and NC-PDACs (69%/82%/93%). CONCLUSIONS Because characteristics of IPMNs remarkably differed between C-PDACs and IC-Ds, another algorithm specific to the early detection of C-PDACs is necessary. Appropriate post-operative managements according to the two types of recurrences may contribute to the improvement in the prognoses of C-PDACs/IC-Ds.
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Affiliation(s)
- Yujiro Kawakami
- Department of Gastroenterology, Sendai City Medical Center, Sendai, Japan; Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Shinsuke Koshita
- Department of Gastroenterology, Sendai City Medical Center, Sendai, Japan.
| | - Yoshihide Kanno
- Department of Gastroenterology, Sendai City Medical Center, Sendai, Japan
| | - Takahisa Ogawa
- Department of Gastroenterology, Sendai City Medical Center, Sendai, Japan
| | - Hiroaki Kusunose
- Department of Gastroenterology, Sendai City Medical Center, Sendai, Japan
| | - Toshitaka Sakai
- Department of Gastroenterology, Sendai City Medical Center, Sendai, Japan
| | - Keisuke Yonamine
- Department of Gastroenterology, Sendai City Medical Center, Sendai, Japan
| | - Kazuaki Miyamoto
- Department of Gastroenterology, Sendai City Medical Center, Sendai, Japan
| | - Fumisato Kozakai
- Department of Gastroenterology, Sendai City Medical Center, Sendai, Japan
| | - Takaho Okada
- Department of Surgery, Sendai City Medical Center, Sendai, Japan
| | - Masaya Oikawa
- Department of Surgery, Sendai City Medical Center, Sendai, Japan
| | - Takashi Tsuchiya
- Department of Surgery, Sendai City Medical Center, Sendai, Japan
| | - Yutaka Noda
- Department of Gastroenterology, Sendai City Medical Center, Sendai, Japan; Department of Pathology, Sendai City Medical Center, Sendai, Japan
| | - Takashi Sawai
- Department of Pathology, Sendai City Medical Center, Sendai, Japan
| | - Hiroshi Nakase
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Kei Ito
- Department of Gastroenterology, Sendai City Medical Center, Sendai, Japan
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45
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Baer JM, Zuo C, Kang LI, de la Lastra AA, Borcherding NC, Knolhoff BL, Bogner SJ, Zhu Y, Yang L, Laurent J, Lewis MA, Zhang N, Kim KW, Fields RC, Yokoyama WM, Mills JC, Ding L, Randolph GJ, DeNardo DG. Fibrosis induced by resident macrophages has divergent roles in pancreas inflammatory injury and PDAC. Nat Immunol 2023; 24:1443-1457. [PMID: 37563309 PMCID: PMC10757749 DOI: 10.1038/s41590-023-01579-x] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 07/11/2023] [Indexed: 08/12/2023]
Abstract
Tissue-resident macrophages (TRMs) are long-lived cells that maintain locally and can be phenotypically distinct from monocyte-derived macrophages. Whether TRMs and monocyte-derived macrophages have district roles under differing pathologies is not understood. Here, we showed that a substantial portion of the macrophages that accumulated during pancreatitis and pancreatic cancer in mice had expanded from TRMs. Pancreas TRMs had an extracellular matrix remodeling phenotype that was important for maintaining tissue homeostasis during inflammation. Loss of TRMs led to exacerbation of severe pancreatitis and death, due to impaired acinar cell survival and recovery. During pancreatitis, TRMs elicited protective effects by triggering the accumulation and activation of fibroblasts, which was necessary for initiating fibrosis as a wound healing response. The same TRM-driven fibrosis, however, drove pancreas cancer pathogenesis and progression. Together, these findings indicate that TRMs play divergent roles in the pathogenesis of pancreatitis and cancer through regulation of stromagenesis.
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Affiliation(s)
- John M Baer
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Chong Zuo
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Liang-I Kang
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
| | | | - Nicholas C Borcherding
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
| | - Brett L Knolhoff
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Savannah J Bogner
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Yu Zhu
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
- Department of Pathology, Stanford University, Palo Alto, CA, USA
| | - Liping Yang
- Division of Rheumatology, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | - Jennifer Laurent
- Division of Rheumatology, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | - Mark A Lewis
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | - Nan Zhang
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
| | - Ki-Wook Kim
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
- Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, IL, USA
| | - Ryan C Fields
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
- Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA
| | - Wayne M Yokoyama
- Division of Rheumatology, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | - Jason C Mills
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
- Departments of Pathology and Immunology and Developmental Biology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- Departments of Medicine, Pathology and Immunology, and Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Li Ding
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA
- McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, USA
- Department of Genetics, Washington University in St. Louis, St. Louis, MO, USA
| | - Gwendalyn J Randolph
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
| | - David G DeNardo
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.
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46
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Hsieh CC, Fu YH, Ku NE, Hsia CC, Hung YT, Hsu TJ, Chen SH, Kuo SJ. The Impact of Chronic Pancreatitis on the Occurrences of Human Cancers: Real-World Data. J Clin Med 2023; 12:5102. [PMID: 37568504 PMCID: PMC10420038 DOI: 10.3390/jcm12155102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 07/29/2023] [Accepted: 07/31/2023] [Indexed: 08/13/2023] Open
Abstract
Chronic pancreatitis (CP) may induce systemic inflammation, potentially increasing cancer susceptibility. However, the link between CP and extra-pancreatic cancer remains underexplored. Employing Taiwanese National Health Insurance Database data from 2000 to 2017, we compared 5394 CP patients with 21,576 non-CP individuals through propensity score matching. CP patients exhibited a significantly higher cancer risk (adjusted hazard ratio (aHR) of 1.32 for females and 1.68 for males) and cumulative incidence (p < 0.001) compared to non-CP individuals. CP showed notable associations with pancreatic (aHR = 3.51), liver (aHR = 1.62), stomach (aHR = 2.01), and other cancers (aHR = 2.09). In terms of liver cancer, CP was significantly associated with patients without viral hepatitis, regardless of gender (aHR = 2.01 for women; aHR = 1.54 for men). No significant cancer occurrences were observed within the first year following CP diagnosis. Pancreatic or liver cancer developed in approximately half of CP patients within 2-3 years, while gastric cancer in male CP patients predominantly occurred around the fifth year after diagnosis. These findings inform potential cancer-screening plans for CP patients.
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Affiliation(s)
- Chi-Chia Hsieh
- Department of Education, Taipei Veterans General Hospital, Taipei 112201, Taiwan;
| | - Yi-Hsiu Fu
- Department of Education, Taichung Veterans General Hospital, Taichung 407219, Taiwan;
| | - Nien-En Ku
- Department of Education, China Medical University Hospital, Taichung 404327, Taiwan; (N.-E.K.); (C.-C.H.)
| | - Chia-Chun Hsia
- Department of Education, China Medical University Hospital, Taichung 404327, Taiwan; (N.-E.K.); (C.-C.H.)
| | - Yu-Tung Hung
- Management Office for Health Data, China Medical University Hospital, Taichung 404327, Taiwan; (Y.-T.H.); (T.-J.H.)
| | - Tzu-Ju Hsu
- Management Office for Health Data, China Medical University Hospital, Taichung 404327, Taiwan; (Y.-T.H.); (T.-J.H.)
| | - Sung-Hsiung Chen
- Department of Orthopedic Surgery, College of Medicine, Chang Gung University, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833401, Taiwan
| | - Shu-Jui Kuo
- School of Medicine, China Medical University, Taichung 404328, Taiwan
- Department of Orthopedic Surgery, China Medical University Hospital, Taichung 404327, Taiwan
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Masson E, Zou WB, Pu N, Rebours V, Génin E, Wu H, Lin JH, Wang YC, Abrantes A, Aguilera Munoz L, Albouys J, Alric L, Amiot X, Archambeaud I, Audiau S, Bastide L, Baudon J, Bellaiche G, Bellon S, Bertrand V, Bideau K, Billiemaz K, Billioud C, Bonnefoy S, Borderon C, Bournet B, Breton E, Brugel M, Buscail L, Cadiot G, Camus M, Causse X, Chamouard P, Chaput U, Cholet F, Ciocan DM, Clavel C, Coffin B, Coimet-Berger L, Creveaux I, Culetto A, Daboussi O, Mestier LDE, Degand T, D'Engremont C, Denis B, Dermine S, Desgrippes R, D'Aubigny AD, Enaud R, Fabre A, Gargot D, Gelsi E, Gentilcore E, Gincul R, Ginglinger-Favre E, Giovannini M, Gomercic C, Gondran H, Grainville T, Grandval P, Grasset D, Grimaldi S, Grimbert S, Hagege H, Heissat S, Hentic O, Herber-Mayne A, Hervouet M, Hoibian S, Jacques J, Jais B, Kaassis M, Koch S, Lacaze E, Lacroute J, Lamireau T, Laurent L, Guillou XLE, Rhun MLE, Leblanc S, Levy P, Lievre A, Lorenzo D, Maire F, Marcel K, Matias C, Mauillon J, Morgant S, Moussata D, Muller N, Nambot S, Napoleon B, Olivier A, Pagenault M, Pelletier AL, Pennec O, Pinard F, Pioche M, Prost B, et alMasson E, Zou WB, Pu N, Rebours V, Génin E, Wu H, Lin JH, Wang YC, Abrantes A, Aguilera Munoz L, Albouys J, Alric L, Amiot X, Archambeaud I, Audiau S, Bastide L, Baudon J, Bellaiche G, Bellon S, Bertrand V, Bideau K, Billiemaz K, Billioud C, Bonnefoy S, Borderon C, Bournet B, Breton E, Brugel M, Buscail L, Cadiot G, Camus M, Causse X, Chamouard P, Chaput U, Cholet F, Ciocan DM, Clavel C, Coffin B, Coimet-Berger L, Creveaux I, Culetto A, Daboussi O, Mestier LDE, Degand T, D'Engremont C, Denis B, Dermine S, Desgrippes R, D'Aubigny AD, Enaud R, Fabre A, Gargot D, Gelsi E, Gentilcore E, Gincul R, Ginglinger-Favre E, Giovannini M, Gomercic C, Gondran H, Grainville T, Grandval P, Grasset D, Grimaldi S, Grimbert S, Hagege H, Heissat S, Hentic O, Herber-Mayne A, Hervouet M, Hoibian S, Jacques J, Jais B, Kaassis M, Koch S, Lacaze E, Lacroute J, Lamireau T, Laurent L, Guillou XLE, Rhun MLE, Leblanc S, Levy P, Lievre A, Lorenzo D, Maire F, Marcel K, Matias C, Mauillon J, Morgant S, Moussata D, Muller N, Nambot S, Napoleon B, Olivier A, Pagenault M, Pelletier AL, Pennec O, Pinard F, Pioche M, Prost B, Queneherve L, Rebours V, Reboux N, Rekik S, Riachi G, Rohmer B, Roquelaure B, Hezode IR, Rostain F, Saurin JC, Servais L, Stan-Iuga R, Subtil C, Texier C, Thomassin L, Tougeron D, Tsakiris L, Valats JC, Vuitton L, Wallenhorst T, Wangerme M, Zanaldi H, Zerbib F. Classification of PRSS1 variants responsible for chronic pancreatitis: An expert perspective from the Franco-Chinese GREPAN study group. Pancreatology 2023; 23:491-506. [PMID: 37581535 DOI: 10.1016/j.pan.2023.04.004] [Show More Authors] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 04/06/2023] [Accepted: 04/13/2023] [Indexed: 08/16/2023]
Abstract
BACKGROUND PRSS1 was the first reported chronic pancreatitis (CP) gene. The existence of both gain-of-function (GoF) and gain-of-proteotoxicity (GoP) pathological PRSS1 variants, together with the fact that PRSS1 variants have been identified in CP subtypes spanning the range from monogenic to multifactorial, has made the classification of PRSS1 variants very challenging. METHODS All currently reported PRSS1 variants (derived primarily from two databases) were manually reviewed with respect to their clinical genetics, functional analysis and population allele frequency. They were classified by variant type and pathological mechanism within the framework of our recently proposed ACMG/AMP guidelines-based seven-category system. RESULTS The total number of distinct germline PRSS1 variants included for analysis was 100, comprising 3 copy number variants (CNVs), 12 5' and 3' variants, 19 intronic variants, 5 nonsense variants, 1 frameshift deletion variant, 6 synonymous variants, 1 in-frame duplication, 3 gene conversions and 50 missense variants. Based upon a combination of clinical genetic and functional analysis, population data and in silico analysis, we classified 26 variants (all 3 CNVs, the in-frame duplication, all 3 gene conversions and 19 missense) as "pathogenic", 3 variants (missense) as "likely pathogenic", 5 variants (four missense and one promoter) as "predisposing", 13 variants (all missense) as "unknown significance", 2 variants (missense) as "likely benign", and all remaining 51 variants as "benign". CONCLUSIONS We describe an expert classification of the 100 PRSS1 variants reported to date. The results have immediate implications for reclassifying many ClinVar-registered PRSS1 variants as well as providing optimal guidelines/standards for reporting PRSS1 variants.
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Affiliation(s)
- Emmanuelle Masson
- Univ Brest, Inserm, EFS, UMR 1078, GGB, F-29200, Brest, France; Service de Génétique Médicale et de Biologie de la Reproduction, CHRU Brest, F-29200, Brest, France
| | - Wen-Bin Zou
- Department of Gastroenterology, Changhai Hospital, The Secondary Military Medical University, Shanghai, China; Shanghai Institute of Pancreatic Diseases, Shanghai, China
| | - Na Pu
- Univ Brest, Inserm, EFS, UMR 1078, GGB, F-29200, Brest, France; Department of Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Vinciane Rebours
- Pancreatology and Digestive Oncology Department, Beaujon Hospital, APHP - Clichy, Université Paris Cité, Paris, France
| | - Emmanuelle Génin
- Univ Brest, Inserm, EFS, UMR 1078, GGB, F-29200, Brest, France; Service de Génétique Médicale et de Biologie de la Reproduction, CHRU Brest, F-29200, Brest, France
| | - Hao Wu
- Department of Gastroenterology, Changhai Hospital, The Secondary Military Medical University, Shanghai, China; Shanghai Institute of Pancreatic Diseases, Shanghai, China
| | - Jin-Huan Lin
- Department of Gastroenterology, Changhai Hospital, The Secondary Military Medical University, Shanghai, China; Shanghai Institute of Pancreatic Diseases, Shanghai, China
| | - Yuan-Chen Wang
- Department of Gastroenterology, Changhai Hospital, The Secondary Military Medical University, Shanghai, China; Shanghai Institute of Pancreatic Diseases, Shanghai, China
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Marc Hervouet
- Hôpital d'instruction des armées Percy, Clamart, France
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Guo K, Zhao Y, Cao Y, Li Y, Yang M, Tian Y, Dai J, Song L, Ren S, Wang Z. Exploring the key genetic association between chronic pancreatitis and pancreatic ductal adenocarcinoma through integrated bioinformatics. Front Genet 2023; 14:1115660. [PMID: 37501719 PMCID: PMC10369079 DOI: 10.3389/fgene.2023.1115660] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 04/19/2023] [Indexed: 07/29/2023] Open
Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) develops rapidly and has a poor prognosis. It has been demonstrated that pancreatic ductal adenocarcinoma and chronic pancreatitis (CP) have a close connection. However, the underlying mechanisms for chronic pancreatitis transforming into pancreatic ductal adenocarcinoma are still unclear. The purpose of this study was to identify real hub genes in the development of chronic pancreatitis and pancreatic ductal adenocarcinoma. Methods: RNA-seq data of chronic pancreatitis and pancreatic ductal adenocarcinoma were downloaded from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) was performed to construct a gene co-expression network between chronic pancreatitis and pancreatic ductal adenocarcinoma. GEO2R and a Venn diagram were used to identify differentially expressed genes. Then visualized networks were constructed with ClueGO, and modules of PPI network were calculated by MCODE plugin. Further validation of the results was carried out in two additional cohorts. Analyses of CEL-coexpressed genes and regulators including miRNAs and transcription factors were performed by using the corresponding online web tool. Finally, the influence of CEL in the tumor immune microenvironment (TIME) was assessed by immune contextual analysis. Results: With the help of WGCNA and GEO2R, four co-expression modules and six hub genes were identified, respectively. ClueGO enrichment analysis and MCODE cluster analysis revealed that the dysfunctional transport of nutrients and trace elements might contribute to chronic pancreatitis and pancreatic ductal adenocarcinoma development. The real hub gene CEL was identified with a markedly low expression in pancreatic ductal adenocarcinoma in external validation sets. According to the miRNA-gene network construction, hsa-miR-198 may be the key miRNA. A strong correlation exists between CEL and TIME after an evaluation of the influence of CEL in TIME. Conclusion: Our study revealed the dysfunctional transport of nutrients and trace elements may be common pathogenesis of pancreatic ductal adenocarcinoma and chronic pancreatitis. Examination on these common pathways and real hub genes may shed light on the underlying mechanism.
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Affiliation(s)
- Kai Guo
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Yatong Zhao
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Yingying Cao
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Yuan Li
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Meng Yang
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Ying Tian
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Jianmeng Dai
- School of Medicine, Tongji University, Shanghai, China
| | - Lina Song
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Shuai Ren
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Zhongqiu Wang
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
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Wan L, Lin KT, Rahman MA, Ishigami Y, Wang Z, Jensen MA, Wilkinson JE, Park Y, Tuveson DA, Krainer AR. Splicing Factor SRSF1 Promotes Pancreatitis and KRASG12D-Mediated Pancreatic Cancer. Cancer Discov 2023; 13:1678-1695. [PMID: 37098965 PMCID: PMC10330071 DOI: 10.1158/2159-8290.cd-22-1013] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 02/14/2023] [Accepted: 03/22/2023] [Indexed: 04/27/2023]
Abstract
Inflammation is strongly associated with pancreatic ductal adenocarcinoma (PDAC), a highly lethal malignancy. Dysregulated RNA splicing factors have been widely reported in tumorigenesis, but their involvement in pancreatitis and PDAC is not well understood. Here, we report that the splicing factor SRSF1 is highly expressed in pancreatitis, PDAC precursor lesions, and tumors. Increased SRSF1 is sufficient to induce pancreatitis and accelerate KRASG12D-mediated PDAC. Mechanistically, SRSF1 activates MAPK signaling-partly by upregulating interleukin 1 receptor type 1 (IL1R1) through alternative-splicing-regulated mRNA stability. Additionally, SRSF1 protein is destabilized through a negative feedback mechanism in phenotypically normal epithelial cells expressing KRASG12D in mouse pancreas and in pancreas organoids acutely expressing KRASG12D, buffering MAPK signaling and maintaining pancreas cell homeostasis. This negative feedback regulation of SRSF1 is overcome by hyperactive MYC, facilitating PDAC tumorigenesis. Our findings implicate SRSF1 in the etiology of pancreatitis and PDAC, and point to SRSF1-misregulated alternative splicing as a potential therapeutic target. SIGNIFICANCE We describe the regulation of splicing factor SRSF1 expression in the context of pancreas cell identity, plasticity, and inflammation. SRSF1 protein downregulation is involved in a negative feedback cellular response to KRASG12D expression, contributing to pancreas cell homeostasis. Conversely, upregulated SRSF1 promotes pancreatitis and accelerates KRASG12D-mediated tumorigenesis through enhanced IL1 and MAPK signaling. This article is highlighted in the In This Issue feature, p. 1501.
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Affiliation(s)
- Ledong Wan
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
| | - Kuan-Ting Lin
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
| | | | - Yuma Ishigami
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
| | - Zhikai Wang
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
| | - Mads A. Jensen
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
| | - John E. Wilkinson
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Youngkyu Park
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
- Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA
| | - David A. Tuveson
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
- Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA
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Zhirong Z, Li H, Yi L, Lichen Z, Ruiwu D. Ferroptosis in pancreatic diseases: potential opportunities and challenges that require attention. Hum Cell 2023; 36:1233-1243. [PMID: 36929283 DOI: 10.1007/s13577-023-00894-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 03/07/2023] [Indexed: 03/18/2023]
Abstract
The pancreas is an abdominal organ with both endocrine and exocrine functions, and patients with pancreatic diseases suffer tremendously. The regulated cell death of various cells in the pancreas is thought to play a key role in disease development. As one of the newly discovered regulated cell death modalities, ferroptosis has the potential for therapeutic applications in the study of multiple diseases. Ferroptosis has been observed in several pancreatic diseases, but its role in pancreatic diseases has not been systematically elucidated or reviewed. Understanding the occurrence of ferroptosis in various pancreatic diseases after damage to the different cell types is crucial in determining disease progression, evaluating targeted therapies, and predicting disease prognosis. Herein, we summarize the research progress associated with ferroptosis in four common pancreatic diseases, namely acute pancreatitis, chronic pancreatitis, pancreatic ductal adenocarcinoma, and diabetes mellitus. Furthermore, the elucidation of ferroptosis in rare pancreatic diseases may provide sociological benefits in the future.
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Affiliation(s)
- Zhao Zhirong
- General Surgery Center, General Hospital of Western Theater Command, No. 270, Rongdu Rd, Jinniu District, Chengdu, 610083, Sichuan, China
- College of Medicine, Southwest Jiaotong University, Chengdu, China
| | - Han Li
- Ultrasound Medical Center, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Liu Yi
- School of Medicine, Jianghan University, Wuhan, 430056, Hubei, China
| | - Zhou Lichen
- General Surgery Center, General Hospital of Western Theater Command, No. 270, Rongdu Rd, Jinniu District, Chengdu, 610083, Sichuan, China
- Pancreatic Injury and Repair Key Laboratory of Sichuan Province, General Hospital of Western Theater Command, Chengdu, Sichuan, China
| | - Dai Ruiwu
- General Surgery Center, General Hospital of Western Theater Command, No. 270, Rongdu Rd, Jinniu District, Chengdu, 610083, Sichuan, China.
- College of Medicine, Southwest Jiaotong University, Chengdu, China.
- Pancreatic Injury and Repair Key Laboratory of Sichuan Province, General Hospital of Western Theater Command, Chengdu, Sichuan, China.
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